Are you involved with planning tech transfer of your drug product? Join this webinar to learn more about the regulations and considerations you need to consider and learnings from a case study. According to 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.” As a result, there is an expectation for transfers to be performed in an organized, methodical manner with appropriate documentation. It is also expected that they happen between one Process Development group to another or to a Pilot Lab, from Process Development lab to clinical or commercial manufacturing, or from Process Development to external clinical manufacturing. Lastly, they may also happen between two company facilities at commercial scale, or between a company and an external contract manufacturing at commercial scale. This presentation will cover points to consider for successful tech transfers with a focus on cGMP training requirements, and include lesson learned from real cases. Presented by Guillaume Plane on September 22, 2016

1. Guillaume PLANE
Provantage
®
End-To-End Solutions
NOT FOR U.S. AND CANADA AUDIENCE
Managing process
scaling and tech
transfer

2. 2 Managing process scaling and tech transfer
Let us start with 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.”
 Transfers have to be performed in an organized, methodical manner, with
appropriate documentation.
 We will focus on the transfer of Drug Substance process parameters and
process knowledge (data).
Technology Transfer

3. 3 Managing process scaling and tech transfer
Process transfers include:
• Transfer from one Process Development group to another, or to Pilot Lab
• Transfer from Process Development to clinical or commercial manufacturing
• Transfer from Process Development to external clinical manufacturing
• Transfer of commercial process between company facilities
• Transfer of commercial process to external contract manufacturing
Greater rigor and documentation are needed for the latter cases, especially transfers between companies.
Best practices discussed here cover the greater level of detail
Scale as appropriate for the situation
Scope of Process Transfers

4. 4 Managing process scaling and tech transfer
Mobius® 2,000 L Single-Use Bioreactor Performances
Production of a mAb with a CHO-S cell line
Define Scale in Advance of Transfer

5. 5 Managing process scaling and tech transfer
Mobius®
2000L Single Use Bioreactor Performances
Production of mAb with CHO-K1 cell line (Cellvento®
CHO 220)

6. 6 Managing process scaling and tech transfer
1. Form tech transfer teams and governance structures, define project charter with goals and timelines
2. Consolidate process knowledge into transferable documentation
3. Gap Analysis / Risk Assessment – leads to detailed project plan
4. Tech Transfer Execution (work the plan)
5. Process “Q/q”ualification – demonstrate technical success
6. Finalize transfer: documentation, support of regulatory activities, follow-up actions, plan for ongoing technical
support, lessons learned
Process Transfer: Key Activities
Transfer does not end at completion of
Qualification lots or approval,
but extends over duration of
manufacturing

7. 7 Managing process scaling and tech transfer
Write Request for Proposal (RFP)
• Provide sufficient detail for accurate assessment
Due Diligence
• Assess capabilities
• Capacity, facility, cGMP, personnel
• High level gap analysis
• Be ready to order long lead time equipment
• Assess feasibility if significant process changes would be required
Write contract
• Be specific on deliverables and expectations
• Ensure terms incentivize rigorous scientific behaviors
Early Planning Stage: often precedes external transfers

8. 8 Managing process scaling and tech transfer
Key content and outcomes from this document must include:
• A well-defined team structure
• Sub-teams for different disciplines
• Connect counterparts
• Establish communication paths
• A well defined governance structure to resolve issues
• Aligned timelines, gating/review points, and goals for deliverables
• Clearly described roles and responsibilities
• Who will be responsible for ongoing support and troubleshooting throughout manufacturing?
• Clearly established success criteria
Set expectations and responsibilities between partners
Project Charter

9. 9 Managing process scaling and tech transfer
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, to focus on intrinsic process
requirements
• 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
Consolidated Process Knowledge
Use an electronic file sharing system
for document hosting– not email

10. 10 Managing process scaling and tech transfer
Additional Valuable Process Information
Materials
• BOM
• Consumables: bags, filters,
tubing, gaskets, o-rings,
etc.
• Vendors
• Grade
Analytics
• Assays used as part of mfg
process: pH, osmo,
conductivity, OD
• Assays required to support
transfer of scale-down
models
Facility & Equipment
Requirements
• URS/FRS
• Heating/cooling
• Process gas flow rates and
total capacity
• Instrumentation and control
capabilities
• Materials of construction
• Safety assessments,
hazardous material
containment/
disposal
Other Sources of
Process Information
• PD reports
• Validation reports
• Batch records / SOPs
• Historical trends of process
and product data
• License requirements
• Small scale model
instructions and data
• Spreadsheet process models
• Tacit knowledge: cell
morphology, media color,
etc.

11. 11 Managing process scaling and tech transfer
Thorough process walk through:
• Based on Process Description document
• Assesses detailed fit of process in receiving facility
• Identifies areas where changes will be necessary or what differences are acceptable
• Guides project work plan
• Identifies needs for facility modifications
Great process learning exercise for the receiving site!
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

12. 12 Managing process scaling and tech transfer
If you have to make 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 decision making- Otherwise, how
do you know if the proposed change is
acceptable?

13. 13 Managing process scaling and tech transfer
Quality Risk Management
What do we do with all these gaps we identified?
Risks are inherent in
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 the risk to quality should be based on scientific
knowledge and ultimately link to the protection of the patient
• The level of effort, formality, and documentation of the quality
risk management process should be commensurate with the
level of risk

14. 14 Managing process scaling and tech transfer
Goal: To achieve readiness for process qualification
Mitigate identified risks
• Equipment/facility modifications and validations
Execute process using small scale model – qualify model
Full scale engineering or “water” runs
Author and approve manufacturing instruction documents
• Requires a well-organized system for tracking and managing edits
Training of production and support staff
Tech Transfer Execution
Work the plan…

15. 15 Managing process scaling and tech transfer
Process “Q/q”ualification
Demonstration that the process is performing correctly at the receiving unit
This may be a formal validation exercise or a simple report following an early clinical campaign
Important to have Pre-defined Success Criteria (may or may not be part of Validation protocol)
• Key Process Performance Metrics
• Step yields, impurities, growth rates, titers, etc.
• Product Quality Ranges
• Successful Validation
At key “go/no-go” decision
points, it is helpful for parties
to have agreed in advance
on what success looks like

16. 16 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
Complete all documentation
Finalize Transfer

17. 17 Managing process scaling and tech transfer
What if you don’t have to make any changes to your process?
Provantage®
End-to-End Value
Existing Process
New Process
Re-fit Process
New Facility
- We develop your manufacturing process for you
- We fit the process to the updated template while your facility is being built

18. 18 Managing process scaling and tech transfer
Provantage®
End-to-End Value
Proven
Templates
Innovation
Knowledge
Transfer
Tech
Transfer

19. 19 Managing process scaling and tech transfer
Template approach
Save time and money thanks to our ClinicReady™ Template
Clarification
Affinity
Chromatography
Ultrafiltration
Sterile filtration
CEX
Chromatography
Bulk
Drug
Substance
Bioreactor
Virus removal
AEX
Chromatography

20. 20
• At each end of stage, a « Gate Review » is performed to ensure that quality of deliverables is online
with the initial target
• The whole stage is then validated
• Intermediates Go/No Go will also occur during a stage to start activities of the next stage
• Allows a time optimization by perfoming tasks in parallel (fast-tracking)
A stage-gate approach

21. 21
Plant Design
Equipment definition
Module definition
Integration
Final modules
Managing process scaling and tech transfer

22. 22 Managing process scaling and tech transfer
Plant Design

23. 23 Managing process scaling and tech transfer
A brand new facility in a little over a year
L0: GMP
Preclinical
production
L+2:
Process
development

24. 24 Managing process scaling and tech transfer
Upstream Suites
Increased flexibility and lower cost production environment

25. 25 Managing process scaling and tech transfer

26. 26 Managing process scaling and tech transfer

27. Tech Transfer
Kick off
meeting
Team
members
Regulatory and
validation
requirements
Technical and
Quality Agreement
Planning
Communication
plan
Risk analysis
validated
Kick off meeting: Scope, transfer timelines and team members are defined
Team members: At least composed of 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 provided
Tech
Transfer
report
Tech
Transfer
Closure
Experiments

28. Goal: Select parameters from cloning to adapt cells to our internal platform for sub-cloning step
Cloning report:
 Draft version: incomplete (raw mat.) / mistakes (% DMSO) but enough data to launch the project
 Cloning medium composition
 Cloning efficiency
 Direct contact with sending entity (SE) for further information (mail exchange)
 Technical transfer for Downstream Processing & Analytical parts but no Upstream part:
 SE did not perform a sub-cloning phase but only a cloning step
 The sub-cloning phase would not be included in a Tech transfer document (SE expertise)
Case study
In-tech transfer of a cell line
Technical transfer
Productivity
assessment
Selection of 3 best clones
Sub-Cloning I
Failed
Tech. meeting
SE/Merck
Media and Feed
Screening
New medium:
ActiCHO
Sub-cloning II
Failed
Technical meeting
SE/M
June 2015 July 2015 Sept 2015 Nov. 2015 March 2016 May 2016

29. Current Working Data
 Final version of cloning report: after review from SE based on Merck comments
 Final version of cell line generation report: provided by Customer in order to know all process of pool generation
 From technical meeting SE/Merck (1)
• Composition of Cloning medium modified. (Gln  Gltmx).
 From technical meeting SE/Merck (2)
• Tech. Transfer document unfilled
• “A” clone has suffered during cloning process=> it is a “difficult” clone => The both failures of sub-cloning are
clone dependent. (and not due to a missing data)
• No defined process of sub-cloning from SE: performing of process dev. for each clone.
• Sub-cloning success rate from SE: 90% for sub-cloning of mAb secreting pool, 80% of failure in case of protein
secreting pool.
Case study
In-tech transfer of a cell line

30. The process has never been running twice within the same template
Robustness of the process has never been demonstrated
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
Process is not robust, even Quality
Attributes of the product
Decision to redevelop a process
Tech transfer is not only related to the transfer of a process,
but to the transfer of a process and its associated issues

31. 31 Managing process scaling and tech transfer
Questions?
Proven
Templates
Innovation
Knowledge
Transfer
Tech
Transfer