1. Analytical Support for Commercial Supply Chain
Optimization of T-DM1/Kadcyla®
Lan Dai, Analytical Development and Quality Control, @ 2015 World ADC Frankfurt

2.  Kadcyla® Bell Ringing on Campus in
Feb, 2013
 CMC Work Continued in Supporting
Post-launch Manufacturing Changes
for Global Commercialization

3. 3
I. Background
1.1 Goal & Challenge
1.2 Product, Process & Supply Chain
1.3 Project Team Governance
II. Analytical Control for Manufacturing Changes
2.0 Overview: Control via Process Validation & Comparability
2.1 Reagents, Starting Materials & Intermediates
2.2 Drug Substance
2.3 Drug Product
III. Summary

4. The Theme: Supply Chain Optimization
4
1.1 Goal and challenge
Goal: Achieve a robust supply chain
CMC Challenges: Overcome ADC unique complexities
Meeting increasing
market demand
Improving supply
chain resilience
DRIVER
1
DRIVER
2
 Establishing work process
• Setting standards
- study, documentation, etc.
• Reaching alignment
- development to commercial
- compliance w/ local site policy
- roles & responsibilities
 Fulfilling global market requirements
 Complex nature of ADCs
 Lack of internal precedents
 Additional outside regulatory
hurdles
SOURCES SPECIFICS
CMC: Chemistry, Manufacturing and Controls

5. Product Info
5
1.2 Product, process and supply chain
 mAb (Trastuzumab, Tmab) + Linker (SMCC) + Drug (Maytansinoids, DM1)
 Lysine conjugates: ~3.5 average Drug to Antibody Ratio
 Lyophilized, 160 and 100 mg/vial, intravenous infusion
 Her2 + metastatic breast cancer; clinical trails ongoing for other indications
 Approval by the FDA and EMA in 2013; global filing ongoing
Drug: Maytansinoid (DM1) Linker: SMCC Mab:
Trastuzumab
(Herceptin®)

6. Complicated Manufacturing Process
6
1.2 Product, process and supply chain
mAb
Drug
Store ≤ -60°C
DS
Release
Testing
Frozen Bulk DS
Linker
Tmab
DM1
SMCC
Drug Product (DP)Drug Substance (DS)
Starting Materials &
Intermediates
DP
Release
Testing
Lyophilized
T-DM1
Aseptic Fill
Lyophilization
Store at 2-8°C
Liquid Tmab
MODIFICATION
Linker
Linker
modified
Tmab
Leaving
group
CONJUGATION
Drug
Formulated
liquid T-DM1

7. Complex Supply Chain (post-launch)
7
1.2 Product, process and supply chain
a: for example, organic solvent used for dissolving SMCC and DM1
Examples of planned changes (scale-up and site transfer)
Tmab
Site Transfer
SMCC
Scale-Up
Site Transfer
DM1
Scale-Up
Site Transfer
Critical Reagents a
Site Transfer
DS
Scale-Up
Site Transfer
DP
Scale-Up
Site Transfer
Drug Product (DP)Drug Substance (DS)
Reagents, Starting
Materials & Intermediates

8. Complex Supply Chain (post-launch)
8
1.2 Product, process and supply chain
Examples of planned changes (scale-up and site transfer)
Tmab
Site Transfer
SMCC
Scale-Up
Site Transfer
DM1
Scale-Up
Site Transfer
Critical Reagents a
Site Transfer
DS
Scale-Up
Site Transfer
DP
Scale-Up
Site Transfer
Drug Product (DP)Drug Substance (DS)
Reagents, Starting
Materials & Intermediates
Many combinations of changes;
Bundling changes to minimize supply chain variants
 Type of change
 Local market/HA requirements
 Study planning (purpose, scope & timeline)
 Integration of filing and supply chain strategies
HA: Health Authority

9. Extensive Team Interactions
9
1.3 Project team governance
GNE: Genentech
CMO: Contract Manufacturing Organization
 Tailored project team setup
ADQC: Analytical development and Quality Control
Tech Dev Team
(GNE/Roche)
DP Team
Small molecule
DS Team
Large molecule
DS Team
Project B
Project A
Project C
 Interactions across sites and with external parties
RocheCMOs
GNE
ANALYTICAL
SUPPORT
 Who we are - ADQC
(development)
 QC method transfer and
management
(commercial)
 QC testing
(commercial)
OTHER SUPPORT
 QA / QA external
 Formulation
 Manufacturing/Process
 Pharm Engineering
 Regulatory
 Leadership (Tech lead
and project manager)

10. 10
I. Background
1.1 Goal & challenge
1.2 Product, Process & Supply Chain
1.3 Project governance
II. Analytical Control for Manufacturing Changes
2.0 Overview: Control via Process Validation & Comparability
2.1 Reagents, Starting Materials & Intermediates
2.2 Drug Substance
2.3 Drug Product
III. Summary

11. Overview: analytical control at all stages
11
2.0 Analytical control for manufacturing changes - Overview
 Control on routine basis:
 Batch release testing
 Selective stability testing
 Control in the event of changes (scale-up/transfer):
 Batch release testing
 Selective stability testing
 Process validation studies
 Comparability studies (change/stage specific)
Drug Product (DP)Drug Substance (DS)
Reagents, Starting
Materials & Intermediates
 Must comply with local regulatory requirements in manufacturers
making post-approval changes

12. 12
I. Background
1.1 Goal & Challenge
1.2 Product, Process & Supply Chain
1.3 Project Team Governance
II. Analytical Control for Manufacturing Changes
2.0 Overview
2.1 Reagents, Starting Materials & Intermediates
2.2 Drug Substance
2.3 Drug Product
III. Summary

13. Demonstration of suitability of new materials
13
2.1 Analytical control for manufacturing changes at reagents, starting materials & intermediates level
Current Analytical Testing Strategy
a: change specific and market specific
Change Category Material Study
Changes w/o
regulatory restriction
Reagents & Starting
Materials:
 Critical reagents
 SMCC
1. reagent stability
2. scale-down use test
3. at-scale comparability
Changes requiring
regulatory submission
Intermediates:
 Tmab
 DM1
1. reagent stability
2. scale-down use test
3. at-scale comparability
4. next-level release /stability
testing a

14. Example of workflow
14
2.1 Analytical control for manufacturing changes at reagents, starting materials & intermediates level
Strategies aligned
at Tech Dev Team
Level
Completion of
study protocol w/
CMO
Execution of
study protocol at
CMO
Completion of
study report w/
CMO
Submission for
regulatory approval
if required
Change is effective
Internal
Committees
Change Proposed

15. 15I. Background
 1.1 Goal and Challenge
 1.2 Product, Process and Supply Chain
 1.3 Project Team Governance
II. Analytical Control for Manufacturing Changes
 2.0 Overview
 2.1 Reagents, Starting Materials and Intermediates
 2.2 Drug Substance
A case study in DS production scale-up
(Example: comparability study )
 2.3 Drug Product
III. Summary

16. DS comparability : a case study in scale-up
16
DS Comparability Protocol
2.2 Analytical control for manufacturing changes at DS level
CoA: Certificate of Analysis
DS release
testing
Quantitative
assessment
Qualitative assessment
Stressed
comparability
Process
related
impurities
 Statistical analysis
on CoA Data
 Selection of CQAs
sensitive to
process changes
 Determination of
tightened
acceptance
criteria with
respect to release
specification
 Intact analysis by
LC-MS
 Reduced analysis by
LC-MS
 Peptide map by
LC-UV
 SEC
 Free maytansinoids
(free drug) by RPLC
 CE-SDS
 iCIEF
 Stressed to
induce
significant
changes
 Comparison of
degradation
profiles
 Homogeneity
analysis of
degradation
rates

17. Consistent profiles in drug load distribution by LC-MS
17
2.2 Analytical control for manufacturing changes at DS level
Reference Material
Old Process
New Process

18. Consistent profiles in peptide map (214 and 252nm) by LC-UV
18
2.2 Analytical control for manufacturing changes at DS level
214nm: full view 252nm: expanded view in drug containing region
New
Process
Old
Process
New
Process
Old
Process
Reference
Material
Reference
Material

19. 19
I. Background
1.1 Goal & Challenge
1.2 Product, Process & Supply Chain
1.3 Project Team Governance
II. Analytical Control for Manufacturing Changes
2.0 Overview
2.1 Reagents, Starting Materials & Intermediates
2.2 Drug Substance
2.3 Drug Product
A case study in DP scale up + site transfer
(Example: process validation & comparability studies)
III. Summary

20. Goal: Assess the impact of residual H2O2 on DP stability & set VHP limit
Study Design
 Various levels of H2O2
 Three temperature conditions: 2-8◦C, 25◦C & 50◦C
 4-year stability program
 Selected CQAs tested, including methionine oxidation
DP Process validation (Example: peroxide spiking study)
20
2.3 Analytical control for manufacturing changes at DP level
 An example of process difference
Vaporized H2O2 (VHP) used to sterilize the filling line at the recipient site, but not at the donor site
 PV studies to address the process difference
Two PV studies to ensure no impact of residual H2O2 on product quality
a) VHP uptake study
b) Peroxide spiking study
CQAs: Critical Quality Attributes

21. LC-MS peptide map to assess methionine oxidation
21
2.3 Analytical control for manufacturing changes at DS level
• Linearity and accuracy (recovery) by a comix study
• Precision (repeatability & intermediate precision) by an extremely
high level sample
• “Change in oxidation” defined based on SD obtained from assay qualification
• ±3SD criteria applied to 1 month interim data, limit determined to be 500ppb
• Ongoing study
• No change at 9month for samples spiked w/ H2O2 ≤ 500ppb under
all 3 temp conditions
ASSAY
QUALIFICATION
ESTABLISHING
VHP LIMIT
CONTINUOUS
MONITORING

22. DP comparability: a case study in scale-up + site transfer
22
2.3 Analytical control for manufacturing changes at DP level
DP Comparability Protocol
 Positive feedback received from HA regarding the strategy prior to execution
DP release
testing
Quantitative assessment Qualitative assessment
Stressed
comparability
 Statistical analysis on
CoA Data
 Selection of CQAs
sensitive to process
changes
 Determination of
tightened acceptance
criteria
Example: Upper limit of free
drug adjusted to account for
process difference (longer hold
time), still far below release
specification
 SEC
 Free maytansinoids
(free drug) by RPLC
 iCIEF
HA: Health Authority

23. Consistent profile in SEC, free drug and iCIEF
23
2.3 Analytical control for manufacturing changes at DP level
SEC
iCIEF
Free drug
Reference Material
Recipient site
Donor Site
Reference Material
Recipient site
Donor Site
Reference Material
(1:2 dilution)
Recipient site
Donor Site

24. Summary
24
 Post-launch CMC Challenges in Optimizing Supply Chain
 Complexity of manufacturing process & supply chain
 Establishing an efficient work process with harmonized business practices/standards
 Fulfilling global market requirements for post-launch changes
 Adequate Analytical Control for Manufacturing Changes at All Stages
 Tailored strategy for each type of change at each stage
 Process validation & comparability studies critical for demonstrating comparable product quality
The Journey of Each Kadcyla® Vial

25. Acknowledgement
25
SM DS
team
DP team
LM DS
team
CMOs
Tech Dev
Team
Product
Dev
Team
Too many contributors to list
ADQC
 Fred Jacobson
 Yan Chen
 Laura Zheng
 Pat Rancatore
 ……
Other Functions
 Andrea Ji
 Yasushi Ogawa
 Mike Geier
 Patrick Devillier
 Hoang Phan
 Jagan Sundaram
 Fred Lim
 Jay Howlett
 Matt Hutchinson
 ……
Roche Colleagues
CMO Team Players
Committee-1
Committee-2
Committee-3

26. Doing now what patients need next
26