how to design your tech transfer system to maintain...
TRANSCRIPT
How to Design Your Tech Transfer System to
Maintain Consistency During a Complete Site
Movement
OTCQB: MBVX
Marvin Peterson, Ph. D.
Sr. Director
Manufacturing
Global Bioproduction Summit
December 13, 2016
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DISCLAIMER
Forward Looking Statements
This presentation contains forward-looking statements and projections. The company makes noexpress or implied representation or warranty as to the completeness of this information or, in thecase of the projections, as to their attainability or the accuracy and completeness of the assumptionsfrom which they are derived, and it is expected that each prospective investor will pursue his, her, orits own independent investigation. It must be recognized that estimates of the company’sperformance are necessarily subject to a high degree of uncertainty and may vary materially fromactual results. In particular, this presentation contains statements, including without limitation theprojections, that constitute “forward-looking statements” within the meaning of the private securitieslitigation reform act of 1995. These statements appear in a number of places in this presentation andinclude, but are not limited to, statements regarding the company’s plans, intentions, beliefs,expectations and assumptions, as well as other statements that are not necessarily historical facts. Thecompany commonly uses words in this memorandum such as “anticipates,” “believes,” “plans,”“expects,” “future,” “intends,” and similar expressions to identify forward-looking statements andprojections. You are cautioned that these forward-looking statements and projections are notguarantees of future performance and involve risks and uncertainties. The company’s actual resultsmay differ materially from those in the forward-looking statements and projections due to variousfactors, including competition, market factors, general economic conditions and those described in the“risk factors” section. The information contained in this presentation describes several, but notnecessarily all, important factors that could cause these differences.
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♦ HuMab Discovery Platform: antibody-based products derived from the human
immune response to cancer
– Developed platform for antibody discovery resulting in portfolio of fully human antibodies
– Early innovator in harnessing the natural human immune system in unique and proprietary ways to
create new products
– Integrated approach to development of cancer diagnostics along with therapeutics
♦ Scientific hypothesis
– Vaccination of patients elicits protective antibody response aimed at killing residual disease
– Natural human antibodies elicited from vaccinations are beneficial for novel targeted, off the shelf,
diagnostics/ therapeutics for patients with cancer
– Tumor-associated carbohydrate antigens present ideal targets for antibody-based therapy not yet
fully exploited
♦ Collaborations
– Memorial Sloan Kettering Cancer Center provides source of patient blood samples for our
discovery efforts, clinical trial site, and manufactures PET imaging clinical materials
– Heidelberg Pharma assists with development of conjugates for ADC program
– Rockefeller University collaborates with development of next generation human 5B1 antibody
– Juno Therapeutics has option to potentially use two binding domains for CAR development
candidates
MABVAX COMPANY BACKGROUND
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MABVAX DISCOVERY PLATFORM: THERAPIES DERIVED FROM THE NATURAL HUMAN IMMUNE RESPONSE
Focused Discovery• Vaccination drives specific
immune response
• Survey response across multiple
patients
• Single B-cell interrogation yields
novel antibodies
• Native human antibodies
generated against validated
vaccine antigens
• Patient samples received from
trials in SCLC, sarcoma,
melanoma, neuroblastoma,
breast, colon, and ovarian
cancers
Screening• Highly efficient screening
against pre-identified targets
• Recovery of fully human
natively paired heavy and light
chains
• Identification of antibodies with
superior selectivity, affinity, and
key characteristics
• Library of fully human
antibodies against multiple
targets
Optimized Therapy• Fully human antibodies have
natural advantages; target
specificity while minimizing
cross reactivity and
immunogenicity
• Integrated development
platform includes
complementary immuno-PET,
diagnostic, ADCs and
radioimmunotherapy
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MABVAX HAS RICH PIPELINE OF POTENTIAL MAB PRODUCTS
Program Target Discovery Pre-IND Phase 1 Phase 2 Commercial Rights
Monoclonal Antibody Programs
MVT-5873 Therapeutic Pancreatic & Colon Cancer1
NCT02672917 WW
MVT-2163 PET-Imaging
Pancreatic & Colon Cancer1
NCT02687230
WW
MVT-1075 Radioimmunotherapy
Pancreatic & Colon Cancer
WW
HuMab 5B1-ADC Pancreatic & Colon
Cancer
WW
HuMab 5B1 – Fc Optimization
Pancreatic & Colon Cancer
WW
HuMab-GD2 Sarcoma & Neuroblastoma
WW
HuMab-GD3 Melanoma, Sarcoma, Neuroblastoma
WW
HuMab-GM2 Multiple Epithelial Cancers
WW
HuMab-Tn Breast cancer WW CAR Programs
Various domains TBD WW
1FDA approved clinical study for pancreatic cancer and other CA19-9 positive malignancies
including colon, lung, breast, stomach and other cancers
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Tech Transfer: The Plan
♦ Process Development and tech transfer targeted for GMP production in stainless steel reactors in US
– CMO near our Clinical Research Site
– 3 demonstration runs at 12L scale
– Fed-batch process CMO had previously demonstrated to be directly scalable to 200L GMP manufacturing
– Typical mAb Process
Upstream
Cell Bank Vial
Seed Train Expansion
Main Bioreactor
Clarification
Downstream
Clarified Harvest
Protein A, Viral Inactivation and Neutralization
AEX Chromatography
CEX Chromatography
Viral Filtration
UF/DF
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Tech Transfer: The Plan Changes
♦ CMO acquired during tech transfer
– No longer will run our production in the US, but will transfer
to another of their acquisitions in Europe
– New quality systems
• 2 acquired sites with their own quality systems integrating
with a 3rd quality group
• New manufacturing equipment
–No stainless steel, all SUBs
–No prior tech transfer knowledge between sites
♦ Required tech transfer to 250L SUB for Toxicology production
♦ Team of consultants
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Tech Transfer: Risk Assessment
♦ Risk Assessment performed across each individual unit
operation
– Minimal, Low, Medium, High rating
– Example: Downstream: 168 minimal, 85 low, 2 medium (255 total)
Step # of parameters
Minimal
Risk Low Risk
Medium
Risk High Risk
To be
verified* Risk Mitigation Actions
Key Accepted low risk differences
development - Tox
Key Accepted low risk differences
development - GMP****
Protein A 92 50 31 0 0 11
* Add mixing instructions in PP for VI titrations (low pH and neutralization) -
row 100 and 101
* Adding pre-use HETP/Ass testing - row 98 and 97
* Document UV meter path length in PP890 - row 84
* Calculate actual # of cycles required in clarified harvest PP - row 25, 87
* Specify in PP890 that step is run at room temperature - row 28
* Correct documentation (PD and TTP) - row 55, row 72, row 78, row 91
* Document and control clarified harvest hold time at RT and 2-8 deg C - rows
83, 85, 86, 87
* Transfer of low pH pool to a secondary
container
* Column packing storage solution
* Column packing qualification buffers
* Column bed height target increased to
maximum of range
* Transfer of low pH pool to a secondary
container
* Column packing storage solution
* Column packing qualification buffers
* Column bed height target increased to
maximum of range
AEX 56 39 9 2** 0 6
* Specify equilibration samples to be pulled right prior to load - row 66
* Document UV meter path length in PP - row 51
* Clarify hold time tracking in PP - rows 63, 64, 64
* Step is a key work horse in the process - evaluting real time performance
evaluation options ***
* Load adjustment dilution w/w vs. v/v
* Sanitization and equilibration residence
time
* Order of operations - 0.2 um filtration post
load adjustment
* Lower Sartobind Q loading - row 38
* Stop collect options***
CEX 91 60 18 0 0 13
* final PP updating/review - wash 2 volume (row 53), pH equil range (row 34)
* Document UV meter path length and start/stop collect in PP - rows 59,60
* Add expiry checks to PP - rows 85, 86
* Add PP instruction to pull equil samples right prior to load - row 88
* Specify dirty column hold time in PP - row 89
* Column packing procedure (solutions,
residence time) -rows 91,95, 98
* Target column bed height increased - row
91
* 2 POROS HS cycles, load adjustment
performed for both cycles at once - row 83
* Column storage solution - row 74
* Target column bed height increased -
row 91
Viral Filtration 46 19 27 0 0 0
* Evaluate harvest/in-process pool amounts of protein to determine if any
pre-emptive actions are required for filter loading (planning for high end)
* Initial filter handling (WFI flush,
sanitization) not performed - rows 12-23
* No filter integrity testing performed - row
45
* Filter sizing planning for going towards
upper end of load rates tested during
development - rows 31, 32, 34
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Tech Transfer Risk Assessment Summary
♦ Outcome was a clear understanding of the path forward, despite
having completely different equipment and analytical methods
for the process we were transferring.
♦ Required much effort in troubleshooting and working our way
around these differences
♦ These tech transfer challenges led to multiple failed batches
♦ Required complete analytical analysis and comparability through
each step in all unit operations before moving forward
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Tech Transfer: The Transfer Moves Forward
♦ Formulation Development showed freezing in PBS led to
aggregation
– In-process sample storage adjusted to 2-8 °C
♦ Control points established downstream
– Viral clearance, aggregation removal
♦ Ran 250L SUB simultaneously with a 5L side run to demonstrate
tech transfer
– Bioreactor scaled based on power per unit volume
♦ Once transfer was demonstrated, scaled for 500L GMP
production
♦ Logistics are critical
– Drug substance in particular
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Cell Growth – Viability and Viable Cell Density
0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Via
bil
ity (
%)
VC
D (
cell
s/m
L)
Time (days)VCD PNJ 12L BRX2 VCD PNJ 12l BRX3 VCD 5L TOX#2 VCD 250L TOX#2 VCD 500L G#1 VCD 500L G#2
Viability PNJ 12L BRX2 Viability PNJ 12L BRX3 Viability 5L TOX#2 Viability 250L TOX#2 Viability 500L G#1 Viability 500L G#2
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Titer
0 2 4 6 8 10 12 14 16 18 20
Tit
er
(g/L
)
Time (days)
PNJ 12L BRX1
PNJ 12L BRX2
PNJ 12l BRX3
5L TOX#2
250L TOX#2
500L GMP#1
500L GMP#2
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Product Quality
Batch Analysis MVT-5873 Drug Substance
12L 250L SUB 500L SUB (GMP)
Test Standard Deviation
Potency: Binding ELISA 9%
SEC (LMW) 0.02%
SEC (Main) 0.01%
SEC (HMW1) 0.00%
SEC (HMW2) 0.03%
CEX: Acidic 1.6%
CEX: Main 5.5%
CEX: Basic 4.6%
Residual DNA 0.98
Residual Protein A 0.23
Residual HCP 0.64
Also compared pH, Osmolality, Identity, SDS-PAGE, Endotoxin, and Bioburden
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The Key Do’s and Don’ts
♦ Insist upon complete analytical analysis
– In-process product comparison across each unit operation and for end product
– Shows product consistency
♦ Risk assessment across each unit operation
♦ Insist upon reports (contractually)– Development
– Tech Transfer
– Campaign
♦ Constant oversite
♦ Frequent site visits during development and engineering
♦ Put a person in plant for GMP runs
♦ Consider strongly the difficulty to troubleshoot and provide oversite of a company on a different continent
♦ DON’T– Go to a CMO being purchased if possible!
Harnessing the Human Immune System To Diagnose and Treat Cancer
MabVax Therapeutics
David Hansen
Paul Maffuid, PhD
Wolfgang Scholz, PhD
Ritsuko Sawada, PhD
Dennis Gately, PhD
Sara Bancroft
Kevin Mudd
Aleksandra Marinkovic-Petrovic
Consultants
Scott Rudge, PhD RMC Pharma
Maria Wik, PhD RMC Pharma
Leticia Sanchez, PhD RMC Pharma
Deborah Quick, PhD RMC Pharma
Raymond Nims, PhD RMC Pharma
Acknowledgements
Research Supported byNIH/NCI CA128362
HHSN261201300060C
NIHR42CA128362