The document discusses the essential aspects of technology transfer and process scaling in biomanufacturing, emphasizing the importance of methodical organization and documentation throughout the transfer process. It outlines a comprehensive methodology for process changes, risk management, and equipment considerations, alongside detailed case studies on transferring stainless steel processes to single-use systems. Key activities include gap analysis, training, and ongoing support to ensure successful tech transfer and regulatory compliance.

1. Merck KGaA
Darmstadt, Germany
Steven Strubbe, Technical Leader, BioReliance® End-to-End
Solutions
Guillaume Plane, Marketing and Development Manager,
BioReliance® End-to-End Solutions
Tips and Tricks from a Biodevelopment Center
Tech Transfer and
Scale-Up

2. Bioreactor Protection with the Viresolve® Barrier Filter | 16 August 2018
The life science business of
Merck KGaA, Darmstadt, Germany
operates as MilliporeSigma
in the U.S. and Canada.
2

3. 3 Managing process scaling and tech transfer
Process transfer is a cornerstone of manufacturing
Process Transfer
Process
development
lab
Pilot lab
Clinical
manufacturing
Commercial
manufacturing
(internal)
Commercial
manufacturing
(external)

4. 4 Managing process scaling and tech transfer
Process transfer is regulatory defined
ICH Q10:
“The goal of technology transfer activities is to transfer product and
process knowledge between development and manufacturing, and
within or between manufacturing sites to achieve product
realization. This knowledge forms the basis for the manufacturing
process, control strategy, process validation approach, and ongoing
continual improvement.”
Process Transfer
 Transfers have to be performed in an organized, methodical manner, with appropriate documentation
 We will focus on the transfer of process parameters and process knowledge (data)

5. Ishikawa diagram
5 Managing process scaling and tech transfer
Process Transfer Methodology
Method Material (Raw) Manpower
Machine (Equipment) Environment (Facility) Measurement
Successful
tech transfer

6. Ishikawa diagram
6 Managing process scaling and tech transfer
Process Transfer Methodology
Method Material (Raw) Manpower
Machine (Equipment) Environment (Facility) Measurement
Successful
tech transfer

7. Ishikawa diagram
7 Managing process scaling and tech transfer
Process Transfer Methodology
Method
Successful
tech transfer
 Tech transfer protocol
 Gap analysis
 Acceptance criteria
 Process knowledge (documentation)
 Risk analysis
 Responsibilities and accountabilities

8.  Form tech transfer teams and governance structures,
 Define project charter with goals and timelines,
 Consolidate process knowledge into transferable documentation,
 Analyze gaps and risks,
 Execute the Tech Transfer: work the plan,
 Demonstrate technical success: Meet Acceptance criteria,
 Finalize transfer: documentation, support of regulatory activities, follow-up actions, lessons learned.
8 Managing process scaling and tech transfer
Process Transfer Key activities

9. 9 Managing process scaling and tech transfer
Process Transfer Key activities
Project Charter
Set expectations and responsibilities between partners
Project charter must include:
 A well-defined team structure
 Sub-teams for different disciplines
 Connect counterparts
 Establish communication paths
 A well defined governance structure to address issues
 Clearly described roles and responsibilities
 Clearly established success criteria

10. 10 Managing process scaling and tech transfer
Process Transfer Key activities
Timeline
Kick off
meeting
Team
set up
Regulatory
requirements,
Technical and
Quality Agreement
Planning,
Risk analysis
Kick off meeting: Scope, transfer timelines and team members are defined
Team members: At least a project manager, a technical leader and a tech transfer team
Communication plan: Deliverables
Team members with their respective responsibilities
Communication flow path
Meeting frequency
Tech transfer protocol: Equipment
Raw materials and consumables
Detailed process description including critical parameters
Analytical methods
Tech Transfer
Protocol,
Reference
material
Tech
Transfer
report
Tech
Transfer
Closure
Experiments

11. A Process Description document with an overview of each step and key process parameters is required
 Information should be described in a site and scale independent manner
 Site-specific details from previous process installations should also be gathered as examples
For example:
 Buffers may have been prepared in batch or via in-line dilution
 Bioreactors may have been operated with different sparger configurations
Process Transfer Key activities
11 Managing process scaling and tech transfer
Consolidated Process Knowledge
Use an electronic file sharing system
for document hosting – not email

12. Process Transfer Key activities
12 Managing process scaling and tech transfer
Gap analysis
Gaps can be addressed by
changing equipment, procedures,
or the process.
Changes may require specific new
validation studies or may be
covered through the Process
Qualification validation.

13. Process Transfer Key activities
13 Managing process scaling and tech transfer
Quality Risk Management
Risks are inherent to
technology transfers
Identifying, assessing, and
mitigating - or - accepting
risks defines the project
work scope of a transfer
From ICH Q9, two primary principles
of quality risk management are:
 Evaluation of risk to quality should be based
on scientific knowledge and ultimately link to
protection of patients
 The level of effort, formality, and documentation of
The quality risk management process should be
commensurate with the level of risk

14. Process Transfer Key activities
14 Managing process scaling and tech transfer
Process “Q/q”ualification
It is a demonstration that the process is
performing correctly at the receiving unit.
It is important to have Pre-defined Success
Criteria: step yield, impurities, titer, etc.

15. Process Transfer Key activities
15 Managing process scaling and tech transfer
Process changes
 Some process changes are inevitable based on
major differences in facility, equipment, or
operational practices.
 Proper experiments must be performed to
determine acceptability of the change. Small-
scale models may be a good tool for examining
the effects of changes.
 Pre-defined success criteria are key to timely
progress and make decisions. Otherwise, how
do you know if the proposed change is
acceptable?

16. Ishikawa diagram
16 Managing process scaling and tech transfer
Process Transfer Methodology
Method Material (Raw) Manpower
Machine (Equipment) Environment (Facility) Measurement
Successful
tech transfer

17. Ishikawa diagram
17 Managing process scaling and tech transfer
Process Transfer Methodology
Machine (Equipment)
Successful
tech transfer
 Scale down model
 Characteristics
 Modelization
 IQ/OQ/PQ

18. Systems characteristics have to be considered
 Mixing efficiency can vary: Impeller type, position, size/tank….
 Sparging efficiency can vary: Sparger size, sparger position, bubble size…
 Fluid movement and G/L interaction can vary: Baffles type, position, interactions
18 Managing process scaling and tech transfer
Equipment knowledge and modelization
3 L 50 L 200 L 2 000 L

19. Systems characteristics have to be considered
 Mass transfer modeling can help
KL.a: Volumetric mass transfer coefficient (s-1)
P/V: Power per unit volume (W.m-3)
Vs: Superficial gas velocity (m.s-1)
19 Managing process scaling and tech transfer
Equipment knowledge and modelization
Design-Expert® Software
Factor Coding: Actual
KLa (hr-1)
Design points above predicted value
Design points below predicted value
34.71
4.07
X1 = A: P/V
X2 = B: Vs
0.000145546
0.000291093
0.000436639
0.000582185
0.000727732
1
4.8
8.6
12.4
16.2
20
0
10
20
30
40
KLa(hr-1) A: P/V (W/m3)
B: Vs (m/s)

20. Systems characteristics have to be considered
20 Managing process scaling and tech transfer
Equipment knowledge and modelization
3 L 50 L 200 L 2 000 L
Design-Expert® Software
Factor Coding: Actual
KLa (hr -1)
Design points above predicted value
Design points below predicted value
22.17
1.88
X1 = A: P/V
X2 = B: Vs
0.00031
0.000568
0.000826
0.001084
0.001342
0.0016
1
4.8
8.6
12.4
16.2
20
0
5
10
15
20
25
KLa(hr-1)
A: P/V (W/M3)
B: Vs (m/s)
Design-Expert® Software
Factor Coding: Actual
KLa (hr-1)
Design points above predicted value
Design points below predicted value
34.71
4.07
X1 = A: P/V
X2 = B: Vs
0.000145546
0.000291093
0.000436639
0.000582185
0.000727732
1
4.8
8.6
12.4
16.2
20
0
10
20
30
40
KLa(hr-1)
A: P/V (W/m3)
B: Vs (m/s)
Design-Expert® Software
Factor Coding: Actual
KLa (hr-1)
Design points above predicted value
Design points below predicted value
29.63
1.91
X1 = A: P/V
X2 = B: Vs
9.17849E-005
0.00018357
0.000275355
0.000367139
0.000458924
1
4.8
8.6
12.4
16.2
20
0
5
10
15
20
25
30
KLa(hr-1)
A: P/V (W/m3)B: Vs (m/s)
-Expert® Software
Coding: Actual
-1)
gn points above predicted value
gn points below predicted value
P/V
Vs
2.26125E-005
3.95718E-005
5.65311E-005
7.34905E-005
9.04498E-005
1
4.8
8.6
12.4
16.2
20
2
3
4
5
6
7
8
9
KLa(hr-1)
A: P/V (W/m3)B: Vs (m/s)

21. Systems characteristics have to be considered
21 Managing process scaling and tech transfer
Equipment knowledge and modelization
3 L 50 L 200 L 2 000 L
Pug/V 10,40 10,48 10,42 10,70
Kla 5,12 5,14 5,16 5,17

22. From 3 L to 2,000 L:
 From Equipment knowledge to Tech transfer and scale-up of any CHO Cell line
22 Managing process scaling and tech transfer
Case study: CHO Cell line
0
10
20
30
40
0 2 4 6 8 10 12 14
VCD(x10^6
cells/mL)
VCD
CHO-M CHO-K1 CHO-S

23. Ishikawa diagram
23 Managing process scaling and tech transfer
Process Transfer Methodology
Method Material (Raw) Manpower
Machine (Equipment) Environment (Facility) Measurement
Successful
tech transfer

24. Ishikawa diagram
24 Managing process scaling and tech transfer
Process Transfer Methodology
Material (Raw)
Successful
tech transfer
 Supplier qualification
 Supply chain
 Regulation

25. Raw material assessment
Type Name Formula CAS # Supplier Manufacturer Reference ID interne Statut Id
MP Potassium Dihydrogenophosphate KH2PO4 7778-77-0 Merck Emprove
Created if
sufficient
grade
OK
Type Name Quality system Capacity Status
MP Potassium Dihydrogenophosphate OK OK OK
Supplier assessment
Global status OK
Type Nom Storage Conditions EHS risk Batch traceability Use statut
MP Potassium Dihydrogenophosphate OK OK OK OK
Use assessment

26. Case study
In-tech transfer of a stainless steel process to single use
PROCESS FITTING
• Load: ≤ 30 g/L
• Mode: Bind/Elute
• 3 wash steps
• Buffer elution: Formic acid
• Elution cond : 8 mS/cm
• Elution volume 6-7 BV
• Load: ≤ 30 g/L
• Mode: Bind/Elute
• 2 wash steps
• Buffer elution: citric acid
• Elution cond : 3.5 mS/cm
• Elution volume < 2.5 BV
Protein A capture
EHS Ok

27. Case study
In-tech transfer of a stainless steel process to single use
PROCESS FITTING
Cation Exchange Chromatography
• Resin
• Load: ≤ 30 g/L
• Mode: Bind/Elute
• Buffer eq: Acetate + NaCL gradient
• Elution cond: 15-20 mS/cm
• Resin
• Load: 500 – 700 g/L
• Mode: overloading
• Buffer eq: Acetate (No NaCl)
• No elution
• Cond 3 mS/cm

28. Case study
In-tech transfer of a stainless steel process to single use
PROCESS FITTING
Anion Exchange Chromatography
• Membrane
• Load dilution: 3X
• Load: 400 g/m²
• Mode: Flowthrough
• Resin
• No dilution
• Load: 300 g/L
• Mode: Flowthrough

29. Ishikawa diagram
29 Managing process scaling and tech transfer
Process Transfer Methodology
Method Material (Raw) Manpower
Machine (Equipment) Environment (Facility) Measurement
Successful
tech transfer

30. Ishikawa diagram
30 Managing process scaling and tech transfer
Process Transfer Methodology
Environment (Facility)
Successful
tech transfer
 Flows in and out
 Equipment limitation
 Storage (raw material, buffer, product)
 Supply (water, gas, etc.)

31. Case study
In-tech transfer of a stainless steel process to single use
Kick off
meeting
Team
members
Regulatory and
validation
requirements
Technical and
Quality Agreement
Planning
Communication
plan
Risk analysis
validated
Tech Transfer
Protocol
Reference
material provided
Tech
Transfer
report
Tech
Transfer
Closure
Experiments

32. Case study
In-tech transfer of a stainless steel process to single use
Kick off
meeting
Team
members
Regulatory and
validation
requirements
Technical and
Quality Agreement
Planning
Communication
plan
Risk analysis
validated
Tech Transfer
Protocol
Reference
material provided
Tech
Transfer
report
Tech
Transfer
Closure
Experiments
 Different equipment
 Different need of supply (No CIP)
 Different need of storage (Bags)
 Different flows in and out

33. Case study
In-tech transfer of a stainless steel process to single use
Kick off
meeting
Team
members
Regulatory and
validation
requirements
Technical and
Quality Agreement
Planning
Communication
plan
Risk analysis
validated
Tech Transfer
Protocol
Reference
material provided
Tech
Transfer
report
Tech
Transfer
Closure
Experiments
3 4 5 6 7 8 9 10 11 12 13 14 15
Titer(g/L)
Production days
200L Mobius 500L stainless steel

34. Case study
In-tech transfer of a stainless steel process to single use
Kick off
meeting
Team
members
Regulatory and
validation
requirements
Technical and
Quality Agreement
Planning
Communication
plan
Risk analysis
validated
Tech Transfer
Protocol
Reference
material provided
Tech
Transfer
report
Tech
Transfer
Closure
Experiments
0
20
40
60
80
100
K7153A
Lot RS10-004
K7153A
Lot N063813001
Abundance%
CEX-HPLC
Main peak Acidic peak Basic peak

35. Case study
In-tech transfer of a stainless steel process to single use
Kick off
meeting
Team
members
Regulatory and
validation
requirements
Technical and
Quality Agreement
Planning
Communication
plan
Risk analysis
validated
Tech Transfer
Protocol
Reference
material provided
Tech
Transfer
report
Tech
Transfer
Closure
Experiments
0.0
20.0
40.0
60.0
80.0
100.0
G0F
Abundance(%)
Most frequent glycan of interest
Drug susbtance from a production with a 500L stainless steel bioreactor
Drug susbtance from a production with a 200L Mobius bioreactor

36. Ishikawa diagram
36 Managing process scaling and tech transfer
Process Transfer Methodology
Method Material (Raw) Manpower
Machine (Equipment) Environment (Facility) Measurement
Successful
tech transfer

37. Ishikawa diagram
37 Managing process scaling and tech transfer
Process Transfer Methodology
Manpower
Successful
tech transfer
 Equipment training
 Process knowledge
 GMP training

38. 38 Managing process scaling and tech transfer
Training
 Process training
1. Scale down the process
2. Train operators in a development lab
 Equipment training
1. Specificities of the receiving site have to be taken into account
2. Training should occur after gap analysis
 GMP training
1. Training of operators should be controlled by QA
2. Traceability is required

39. Ishikawa diagram
39 Managing process scaling and tech transfer
Process Transfer Methodology
Method Material (Raw) Manpower
Machine (Equipment) Environment (Facility) Measurement
Successful
tech transfer

40. Ishikawa diagram
40 Managing process scaling and tech transfer
Process Transfer Methodology
Measurement
Successful
tech transfer
 Method transfer
 Method validation
 Analytical transfer / Qualification

41. 41 Managing process scaling and tech transfer
Measurement
 Process analytics should be transferred at first
 Scale-down model of the process may help save money, time and resources
 Qualification of reactants is key

42. 42 Managing process scaling and tech transfer
Review process performance
• If there are issues to be corrected, assign actions and plan the work
• If failures occurred due to flaws in the methods of transfer, amend
transfer procedures for future executions
Support Regulatory activities
• Document preparation for submissions
• Respond to questions
• Preparation for inspections
Implement systems for ongoing technical support of manufacturing
Finalize Transfer

43. The vibrant M and BioReliance are trademarks of Merck KGaA, Darmstadt, Germany or its affiliates. All other trademarks are the property of their respective
owners. Detailed information on trademarks is available via publicly accessible resources.
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