Authored and Presented by: Niket Bubna, Ph.D

1. Confidential
Speed to GMP:
Moving from Rapid Process
Development to High
Throughput Tech Transfer
Niket Bubna
Presented at
257th ACS National Meeting 2019
Orlando, FL

2. 2
Confidential
Who We Are
Background
How we Tech Transfer?
Tech Transfer Case Studies
Conclusions
Outline

3. Confidential
4
Who We Are
• Analytical & Formulation Services, Microbial, Mammalian & Cell Therapy CDMO
• CDMO services first offered in 2004
• Acquired by JSR Corp in 2015
• Highly experienced Executive & Management Teams
• Excellent Track Record & Client Satisfaction
KBI Biopharma’s mission is to accelerate the development of innovative discoveries into life-
changing biological products & expand global access of medicines to patients in need

4. Confidential
5
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
KBI’s North America Locations
March 2018
Louisville, CO (2018)
Elion Labs
• Analytical Technologies
• Leading Biophysical Chara

5. Confidential
6
SelexisKBI
Selexis – Geneva, Switzerland (2017)
Affiliate of KBI
Best in class cell line development &
candidate selection technologies
KBI Leuven, Belgium (2018)
Analytical, Formulation and QC services for
GMP & non-GMP product testing
European Locations

6. Confidential
7
Rapid process development and manufacturing approach for faster IND
submission is often being used for biologics
• What role does KBI play in enabling faster delivery of products to the clinic?
• What strategies are employed for rapid process development?
• Can manufacturing readiness be accelerated?
Speed to GMP/IND

7. Confidential
8
Biologics CMC & Rapid Process Development
FIH CMC
Speed to GMP/IND using SKI
• Platform cell line
• Platform cell culture and downstream
processes
• Standard scale-up manufacturing
operations
Selexis KBI Integrated Development Approach

8. Confidential
9
KBI-NC has been supporting ~10 IND/IMPD filings per year since 2015
What is needed to accelerate manufacturing of biologics?
Types of Mammalian Manufacturing Projects
mAb, 45.1%
Fc-fusion,
Fusion, 9.8%
Bispecific,
21.6%
Recombinant
Protein, 5.9%
Glycoprotein
vaccine,
13.7%
Enzyme,
3.9%

9. Confidential
10
Questions to Consider
• How is tech transfer performed within a CDMO?
• Multi-product facilities
• Phase I to Phase III projects
• Are there standard approaches that ensure 100% success?

10. Confidential
11
• Key goal is to ensure seamless transfer of process parameters, raw materials
and process knowledge for cGMP manufacturing
• Initiate process transfer while process development is on-going; 4-5 months
prior to manufacturing start
• Need to reduce gaps in equipment and raw material grades between
development and manufacturing
• Use of platform upstream and downstream processes minimizes changes in
manufacturing operations
• Templated documents for process transfer and manufacturing ops
Tech Transfer Business Process: Considerations

11. Confidential
12
• Tech transfer milestones defined with T=0 as
cell culture vial thaw or harvest
• Process descriptions, batch record review and
floor support are key deliverables from
process development
Tech Transfer Business Process

12. Confidential
13
Case Study: SKI Tech Transfer
Passage 4 (N-2)
50 L Wave Cellbag
Passage 3
5 L Shake Flasks
Passage 2
500 mL Shake Flasks
Production bioreactor
(XDR-2000)
Passage 5 (N-1)
(XDR-200)
Vial thaw - Passage 1
125 mL Shake Flask
Process Parameter Process Value
Temperature Platform
Temp Downshift Platform
DO Platform
pH Control Platform
pH Shift Variable
Agitation Fixed P/V
Air Sparge Fixed VVM
Air Overlay Fixed HVM
Basal Medium Platform
Target Seed Density Variable
Base for pH Control Platform
Feed Medium Platform
Supplement Platform
Harvest Criteria Variable
• Inoculum train duration and parameters (temperature, agitation
and CO2 %) are fixed for all SKI cell lines
• Several production bioreactor parameters (for e.g. temperature
set point, DO set point, seed density) are consistent among SKI
processes
• Nutrient medium and feed media are fixed for all SKI cell lines
• Product-specific nutrient supplements or process parameters
can be included
• Process duration is generally 14 days – range of 12-16 days
depending on desired QTPP

13. Confidential
14
SKI Tech Transfer
0 2 4 6 8 10 12 14 16
Viability
VCC
Days
200 L PD Run VCC 1000 L cGMP VCC
200 L PD Run Viability 1000 L cGMP Viability
0 2 4 6 8 10 12 14 16
pCO2
pH
Days
200 L PD Run pH 1000 L cGMP pH
200 L PD Run pCO2 1000 L cGMP pCO2
ProATiter
Days
200 L PD Run 1000 L cGMP
0 2 4 6 8 10 12 14 16
Lactate
Glucose
Days
200 L PD Run Glc 1000 L GMP Glc
200 L PD Run Lac 1000 L GMP Lac
0 2 4 6 8 10 12 14 16
Ammonia
Glutamine
Days
200 L PD Run Gln 1000 L GMP Gln
200 L PD Run Amm 1000 L GMP Amm
Scale-up into a 2000 L SUB
from the 200 L process
development scale is
seamless and provides
reproducible cell culture
performance

14. Confidential
15
• Difficult to develop a standard platform processes for manufacturing non
antibody products
• Changes to basal medium, feeds, chromatography resins, buffers can be
frequently necessitated to achieve desired productivity and product quality
• Final process tested in same scale bioreactors prior to start of cGMP
manufacturing
• Developed and manufactured a series of gp120 vaccine proteins in CHO cell
lines where first molecule required changes to manufacturing operations, but
subsequent molecules were transferred as a ‘platform’ process
Case Study: Non-mAb Tech Transfer

15. Confidential
16
Examples for non-standard process
steps
• No seed bioreactor operations: no
seed bioreactor (production bioreactor
inoculation using shake flasks
• Vendor liquid for all raw materials
• No use of single-use BPC bags
• Deed and supplement addition based
on cell growth,
• Harvest day dependent on cell growth
and viability
Non-mAb Tech Transfer
Production Bioreactor
(XDR-200 SUB)
Harvest Clarification
(Depth Filtration)
Vial Thaw (Passage 1)
InoculumExpansionProduction&Recovery
4 days
12-14 days
Shake Flask Passages
(Passage 2-5)
14 days
Cell Culture & Harvest Process

16. Confidential
17
• Commercial process development and commercial launch manufacturing is
often being expedited
• Limited changes from FIH to commercial processes to reduce time required for
BLA filing
• Follow same approach as FIH process transfer, but provide NOR
definition and FMEA RA to enable CPP and critical raw materials
assessment
• Important to develop qualified scale-down models to support PPQ readiness,
commercial manufacturing and CPV
• PPQ campaign performed using initial risk and criticality assignments; PAR
updated post-PPQ using PC data package
Case Study: Tech Transfer for Commercial Manufacturing

17. Confidential
18
Tech Transfer for Commercial Manufacturing
PAR
Equivalence testing between
SDM & at-scale performance
Post-PC Tech Transfer
cGMP n=10
SDM n=5
Pre-PC Tech Transfer
0 2 4 6 8 10 12 14 16
Day
ambr250 (n=3) 3 L Scale (n=9)
200 L PD (n=3) 2000 L cGMP (n=10)
6 8 10 12 14 16
Day
ambr250 (n=3) 3 L Scale (n=9)
200 L PD (n=3) 2000 L cGMP (n=10)

18. Confidential
19
• Platform-based process development is an important starting point to
streamline process transfer and manufacturing operations
• Need to ensure process scalability at pilot-scale prior to GMP manufacturing
• Equipment and raw materials must be aligned between process development
and manufacturing
• Minimize changes to standard practices, equipment platforms and document
templates
Does each new process require a ‘full’ tech transfer?
Focus only on non-platform, non-standard process changes
Key Takeaways

19. Confidential
Questions?
Visit us at http://www.kbibiopharma.com