3. 4
Durham, NC (2004)
Mammalian
• Clinical & Commercial (pre-PAI)
cGMP Manufacturing
• Analytical, Formulation, Stability & QC
• Mass Spec Core Facility
• Cell Based Assays
Boulder, CO (2014)
Microbial
• Strain Development
• Process & Analytical Development
• Clinical & Commercial (Approved)
cGMP Manufacturing
• QC, Analytical, Formulation, Stability
• Particle Characterization Core
RTP, NC (2013)
Venture Center, NC (2018)
Mammalian
• Cell Line Development
• Process & Analytical Development
• Process Characterization
• Small scale Process Validation
The Woodlands, TX (2017)
Cell Therapy
• Process and Analytical Development
• cGMP Manufacturing & Testing
• Cell Based Assays
San Diego, CA (2017)
Alliance Protein Labs
• Analytical Technologies
• Leading AUC expertise
KBI Sites
North America Locations
March 2018
Louisville, CO (2018)
Elion Labs
• Analytical Technologies
• Leading Biophysical Chara
4. Confidential
5
SelexisKBI
Selexis – Geneva, Switzerland
(2017 – an affiliate of KBI)
Best in class cell line development &
candidate selection technologies
Leuven, BE (2018)
Analytical, Formulation and QC services for
GMP & non-GMP product testing
European Locations
5. Confidential
6
Large number of biologics under development and regulatory review
Expedited drug development; rolling and priority review can be requested
Biologics & Breakthrough Designation
Ref: CDER Breakthrough Therapy Designation Requests Received by Fiscal Year (As of 31 December 2018)
Ref: The Biopharmaceutical Pipeline: Innovative Therapies in Clinical Development (July 2017)
0
20
40
60
80
100
120
140
160
2012 2013 2014 2015 2016 2017 2018
Total Requests Received Granted
Breakthrough Biopharmaceuticals
6. Confidential
7
Typically carrying out process
development and scale-up
manufacturing for >10 new
biologics each year
Several products from 2013-15
are now under commercialization
Breakthrough and Fast Track
designation products under
commercialization
New Biologics IND/IMPD
0
5
10
15
20
25
30
35
2013-14 2015 2016 2017 2018
New Products Mfg Batches
KBI Mammalian Manufacturing Plant (Durham, NC)
7. Confidential
8
• Platform-based process development
• Commercialization to focus on specific improvements like titer or yield
Biologics CMC & Timelines
FIH CMC Timeline
8. Confidential
9
• Single-use for entire cell culture manufacturing process
• Bioreactor agitation and gassing scale-up is heavily dependent on preset
factors like tip speed, P/V, kLa, volumetric gas flow
KBI Mammalian Cell Culture Manufacturing Platform
Parameter XDR-50 SUB XDR-200 SUB XDR-2000 SUB
Impeller Diameter 0.2159 m 0.2159 m 0.4191 m
Impeller Power Number 1.50 1.15 0.72
Pitched-blade Impeller 3 blades at 40° 3 blades at 40° 4 blades at 40°
Turn-down Ratio 2.2:1 5:1 5:1
Aspect Ratio 1.5:1 1.5:1 1.5:1
9. Confidential
10
• Go small-scale and high throughput route for maximum steps
• Single-use bioreactors for process development and manufacturing
• Efforts for miniaturization, especially in bioreactor systems have resulted in
several products in the market
High Throughput & Single-use Technologies for Cell Culture PD & PC
10. Confidential
11
• Test SDM during Phase I/III process development
• Carry out PC for different unit operations in parallel
• Leverage Phase I experience and FMEA RA to design PC
• Aim to complete main PC stages and key experiments for first
submission
• Consider using pilot-scale runs to qualify harvest SDM
• Use high throughput tools for experiments
• Deploy statistical analysis using JMP, Design Expert etc. where possible
• Consider MVDA for large data sets like at-scale or SDM runs
Accelerated PC & SD-PPQ Timelines: Our Approach
11. Confidential
12
• LIVCA – Carry out with commercial launch process cGMP runs
• Medium-Feed Stability Study – Define stability time points with practical use
• Raw Material Qualification – Aim to test within PC and leverage PD results
• Worst-Case Linkage (Production/Harvest with Downstream)
Accelerated PC & SD-PPQ Studies: Our Approach
12. Confidential
13
Important to test proposed scale-down model during commercial process
development to ensure success in SDMQ and PC. Cell bank and scale-
dependent parameters like agitation and gassing should be tested. Focus on
matching CPPs and cell culture process outcomes
Establishing SDM
13. Confidential
14
• Equivalence testing on SDM; comparison
with cGMP results
• Need to establish acceptable difference
between scale-down models and cGMP
• Consider to establish ‘offset’ for known
differences in factors like doubling time or
a pCQA
Establishing SDM
14. Confidential
15
• Scale-down models are established using scale-dependent parameters including agitation and
gassing, which use P/V, kLa, tip speed, vvm, etc.
• Scale-down approaches in ambr250 do not necessarily use equivalent P/V or kLa values
Establishing SDM in ambr250
15. Confidential
16
Important to mimic at-scale cellular environment to obtain a robust scale-down model
Establishing SDM in ambr250
Key parameters
pH control
DO control
Temperature control
Feed addition
Titer (g/L)
16. Confidential
17
• Impact of sampling in ambr250 is larger when compared with at-scale runs
• Adjust feeding strategy to provide nutrient levels similar to at-scale
Establishing SDM in ambr250
Key parameters
pH control
DO control
Temperature control
Feed addition
17. Confidential
18
Matching cell growth, metabolite profiles is
important to qualify SDMQ using pre-
determined criteria including CPP and pCQAs
Establishing SDM in ambr250
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
VCC(e^6cells/mL)
Time (days)
Control Avg (n=3) Control 2 Avg (n=3) Pilot-Scale 200 L (n=3)
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Lactate(g/L)
Time (days)
Control Avg (n=3) Control 2 Avg (n=3) Pilot-Scale 200 L (n=3)
18. Confidential
19
Predicting CPP and pCQA Performance
DOE OFAT
cGMP
SDM
Over
feedingPlanned
Excursion
Extended
Medium
HoldTiter
Response for a CPP over production PC
test conditions
SDM within cGMP range
DOE to be analyzed for design space and
prediction model
OFAT conditions show impact of stress
factors
19. Confidential
20
Response for a glycan peak from
production PC study
SDM within cGMP range
cGMP results within BDS specification range
Reduction in %peak area correlated with
test conditions
Predicting CPP and pCQA Performance
cGMP
SDM
CP
N-glycan peak (BDS Spec)
DOE Hi Condition
Planned Excursion
Hi DO
20. Confidential
21
DOE models used to generate prediction profile across tested process range
Process control strategy update – NOR and PAR
Predicting CPP and pCQA Performance
NOR
PAR
21. Confidential
22
• Preceded by commercial process development and pilot-scale (200 L) runs
• Upstream is rate-limiting
• Downstream PC can be accelerated with equipment and resources
• Draft CSD prepared based on historical development data
• PPQ campaign performed in parallel with PC
• Control Strategy is updated post-PC
Accelerated PC and SD-PPQ Timelines
22. Confidential
23
• Process development approach and SDM establishment are important for PC success
• Implement parallel PC execution of several unit operations
• Deploy high throughput approach for maximum operations including analytical testing
PC and SD-PPQ data package to support BLA submission can be achieved in 9 months
Concluding Remarks
Meaningful PC Factors
Mix of DOE & OFAT
DOE for Interactions only
Separate Raw Material
Experiments
Use FMEA RA
Predictable SDM
Mimic at-scale environment:
pH & DO Control
Feed addition
CPP & pCQA Equivalence
Robustness
Reproducibility
Benefits of ambr250 SDM
High throughput
Accuracy
Resource Efficiency
Process monitoring
Data collection
Accelerating PC Timelines
Parallel Experiments
High Throughput
Workflow
Pre-PC Studies during PD
Leverage Ph I/II Data
Pilot-scale Runs PC
2-3 FMEA RA