Technology
gy Transfer
Herwig Kapeller, Novartis Pharmaceuticals Corp.
September 10, 2009
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Agenda
g
• What is a Technology Transfer
• Structures for Success – Transfer Plan
• Case study 1: Transfer of an improved process
from Development into Production
• Case study 2: Transfer of a recombinant protein
from 3rd party production into Novartis production
• Lessons learned
September 10, 2009
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Technology
gy Transfer
• Transfer all the knowledge
g needed to
perform a given biotech process from a
Transferring Site to a Receiving Site
¾ Transfer processes from Development into Production
¾ Transfer processes from one No
Novartis
artis site to another
Novartis site
¾ Transfer of processes from other Biotech/Pharma
companies into Novartis
¾ Transfer processes from Novartis to 3rd parties
September 10, 2009
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Novartis Biopharmaceutical
O
Operations
ti
- BPO
September 10, 2009
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BPO - Transfer Plan
•
•
•
•
•
•
•
•
•
Transfer strategy
gy
Timelines and key milestones
Transfer costs
Organization and responsibilities
Transfer acceptance criteria
P
Process
d
description
i ti
Status evaluation and gap analysis
Process adaptations at the receiving site
Equipment adaptations at the receiving site
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Transfer Strategy
gy
• Description of the process being transferred and
whether a change in scale is involved with the site
transfer
• Risk Assessment whether the process transferred
fits into the facility of the receiving site
• Possible process adaptations or equipment
adaptations of the receiving site
• On site Training of RS people at TS before transfer
and at RS during engineering runs
• How many technical transfer batches in small-scale
pilot-scale
bioreactors/fermenters and lab-scale or p
DSP equipment
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Transfer Strategy
gy
• Number of engineering
g
g and GMP batches at largeg
scale
• Need for a pre-comparability study with material
f
from
the
th pilot-scale
il t
l technical
t h i l transfer
t
f batches
b t h
prior to the start of the large-scale campaign
• Which batches manufactured at the transferring
site will be included in the comparability study
• Need for validation studies, what needs to be
repeated
t d
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Phases of Technology
gy Transfer
Information Transfer
Analytical Phase
Pilot Phase
Scale Up
M
Manufacturing
f t i
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Organization
g
and Responsibilities
p
• Define who is responsible for what
• Leave no interpretation room
• Responsibility list (e.g. RACI chart)
• Full responsibility for the manufacture of the
batches and the process itself is transferred to the
receiving site or some activities remain with the
transferring site?
• Discuss responsibilities in case process
adaptations have to be made.
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Transfer Acceptance
p
Criteria
• These criteria will depend on the phase of
development – obviously the more advanced the
project, the more detail will be required.
• The
Th transfer
f acceptance
criteria must be agreed by
the transferring
g and receiving
g
sites prior to the start of the
transfer.
• Involve
In ol e QA and RegCMC
Title of test
Specification
Properties
Appearance of lyophilizate
1)
Color of solution
Solubility
White or almost white powder
Report result
Freely soluble in water
Identity
Identity b y N-terminal amino acid sequence
Identity b y HPLC
Identity b y Trypsin digest (Peptide Mapping)
Positive identity
Positive identity
Positive identity
Purity
Purityy b y HPLC
Related substances by HPLC
≥ 95.0 % ((area))
≤ 3.0 % (area) for any single peak
≤ 5.0 % (area) for all peaks
≥ 95.0 % (area)
≤ 3.0 % (area) for any single peak
≤ 5.0 % (area) for all peaks
≤ 3.0 % (area) for N-acetyl-Cys1-CT (impurity A)
Purity b y CEX
Related Substances by CEX
≤ 0.6 % (area) for Gly-CT (impurity E)
≤ 0.2 % (area) for SO3-CT (impurity F)
≤ 0.2 % (area) for SO3-Gly-CT (impurity G)
Related Substance (Dimer) of sCT by SE-HPLC
1)
Bacterial endotoxin (LAL)
Bioburden
Ethanol
Report main peak % (area)
Report dimer peak % (area)
≤ 25 EU/mg sCT
≤ 100 cfu/100 mg sCT
≤ 0.5 %
Assay
September 10, 2009
Assay by HPLC
Water content
Acetic Acid content
≥ 80.0 % (w/w)
≤ 10.0 %
4.0 – 15.0 %
Sum of contents of Acetic Acid + Water
≤ 20 %
Potency
Potency determination by cAMP ELISA with T47D cells
≥ 5000 IU/mg of peptide
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Process & Equipment
q p
Adaptations
p
• Based on status evaluation and g
gap
p analysis
y
• Goal is to fit the process into the facility at the
receiving site
• Aim is to keep process and resulting product
quality the same
• Depending on phase of product possibilities for
changes may be limited
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Need for Adaptations
p
• Amount of available vessels vs. disposable
t h l
technology
• Volumes of vessel (e.g. volume of seed vessel
too small,
small change process or change equipment,
equipment
change transfer criterion, additional studies)
• Corrosion (e.g.
(e g trace element solution in HCl - in
glass flasks at lab scale, steel tanks at
manufacturing scale)
• Accuracy of feed rates (e.g. glucose feeding at
start required lowest pump rate, could not be
realized with mass flow at manufacturing scale)
September 10, 2009
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Process & Equipment
q p
Adaptations
p
• Exactly the same raw materials might not
be available
• Quality may vary despite the same
specification
• A hi
higher
h quality
lit material
t i l is
i nott always
l
better
b tt
September 10, 2009
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Case Study 1 – Development
V
Vacaville
ill to
t Production
P d ti Vacaville
V
ill
Extracellular recombinant protein in yeast
Simple
p process:
p
• Fermentation
• Centrifugation
• Filtration
• Capture Chromatography
• Concentration
C
t ti
September 10, 2009
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Case Study
y 1 – Fermentation
• Process developed early 1990
• Successfully running at 12k production scale
• Process improvements identified
•
•
•
•
Small scale model in 20L lab scale developed
36 experiments to establish Design Space
Fermentation with an exponential feed profile
Abbreviated transfer plan due to existing process
knowledge
September 10, 2009
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Case Study
y 1 – Fermentation
•
•
•
•
•
•
•
•
•
Transfer strategy
Timelines and key milestones
Transfer costs
Organization and responsibilities
Transfer acceptance criteria
Process description
Status evaluation and gap analysis
Process adaptations at the receiving site
Equipment adaptations at the receiving site
September 10, 2009
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Case Study
y 1 – Fermentation
• First test rruns
ns at scale “failed”
• Altered growth behavior
• Altered ethanol metabolism & productivity
Main Culture - Cell Growth
30
OD failing
f ili run
100
25
OD good run
80
20
[Ethanol] good run
60
15
`
40
10
20
5
0
[[Ethanol] (g/L)
Optical Density
O
[Ethanol] failing run]
0
0
10
September 10, 2009
20
30
40
runtime (h)
50
60
70
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Case Study
y 1 – Fermentation
• Structured
Str ct red Root Ca
Cause
se Anal
Analysis
sis
• Glucose Feed changed
• ADH promotor in cells is highly glucose
sensitive
• Local g
glucose concentration gradients
g
• Experimental mixing time 7 - 9 minutes
• Cells are “switching on and off”
¾ Improve mixing at scale
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Case Study
y 1 – Fermentation
¾ Process & Equipment adaptations at the
receiving site
• Agitation
g
rate increased
• Glucose feed line submerged
Did we succeed?
September 10, 2009
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Case Study
y 1 – Fermentation
• More Root Ca
Cause
se Anal
Analysis
sis
• Signs of limiting nutrient
•O
One off the
th complex
l raw materials
t i l had
h d
slightly changed in respect to its
composition
p
¾Addition of a larger amount of trace
elements
September 10, 2009
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Case Study 2 – Production 3rd party
t Production
to
P d ti Novartis
N
ti
Extracellular recombinant protein in yeast
More complex
p
process:
p
• Fermentation
• Centrifugation
• Multiple Chromatography Steps
• Concentration
September 10, 2009
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Case Study
y2
• Process successfully running at 3rd party
20k production scale for years
• Fermentation employs a sophisticated dissolved
oxygen/pH depending glucose feed control
• Transfer to 40k scale via pilot phase at Sandoz
Kundl
• Excellent process description available
• 3rd party supports transfer with experienced on
site
it personnell
• Successful transfer into pilot phase
September 10, 2009
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Case Study
y2
• First test rruns
ns at scale “failed”
• Growth behavior comparable
• Productivity only 20%
September 10, 2009
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Case Study
y2
• Structured
Str ct red Root Ca
Cause
se Anal
Analysis
sis
• Calibration of DO probes is different
• 2nd Agitator blade hits the surface just at the
time of induction
September 10, 2009
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Case Study
y2
• Adaptations
¾ Change criteria for DO to accommodate
for different calibration of probes
¾ Change starting volume
¾ Change position of agitator blades on
shaft
September 10, 2009
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Lessons Learned
• People & Communication
• Face-to-face kick-off meeting
• Visit transferring site and watch process
• Physical presence of experts from the transferring
site during first runs
• Understand process complexity
• Equipment / Facilities
• Detailed knowledge of the technical set
set-up
up of the
receiving site needed
• Availability of Lab and pilot plant resources
September 10, 2009
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Lessons Learned
• Materials & Methods
• Analytical transfer phase often underestimated
• Include information about what can go wrong, which
points should be carefully watched in tech transfer
documents
• Information about the origin of limits and
parameters
• Processes
• A structured
structured, well defined approach saves time and
money
• Anticipate
p
changes
g from outside your
y
control area
September 10, 2009
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Lessons Learned
• Questionnaire to gather information
• Group meetings to finalize the output
Background
(Issue(s) faced within the project or the team)
Chosen Management
(What did you chose to do about the issue and why?)
What was done well/not done well?
Why do you think things went well/did not go well?
What should be done similarly next time?
What could be improved next time?
Are there any generalizable LLs to be gained from this experience?
(List actionable LLs)
Key words:
((for archiving
gp
purposes)
p
)
September 10, 2009
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Acknowledgements
g
•
Novartis Vacaville Manufacturing Technology & Engineering
Gabriel Batey, Matt Colemann, Ross Cox, Ji-eun Lee, Viki Levi, Julie
McKnight, Michael Plesha, Peter Tan, Diana Tierra, Kent Xu, Xiaoyue
Zhu, Korchang Hsu
•
Sandoz Kundl Development
Klaus Graumann, Bettina Knorr, Norbert Palma, Gerhard Schneider
September 10, 2009
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