biopharmaceutical manufacturing at lab scale
TRANSCRIPT
27 June 2019, BPSA European Advisory Council F2F Meeting
Ahd Hamidi, Head Global Health projects
Biopharmaceutical Manufacturing at Lab ScaleAdvantages of Highly Intensified Processing
Agenda
Impact of vaccination
Polio containment
Highly Intensified processing: sIPV
About us
Impact of vaccination
Vaccines have a major impact on global health
‘Vaccination is one of the most cost-effective healthcare interventions,
preventing almost 6 million deaths annually worldwide.’
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Reported Estimated
Global Polio cases
1985-2016
Global Smallpox cases
1920-2010
Source: World Health Organization Disease eradication is a fact
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About 8210 people die every day due to preventable diseases
Source: World Health Organization
In case of 100% immunization coverage, 1 out of 7
deaths among young children could be prevented
with vaccines
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Health Gap
Price of the vaccine
Financial sustainability
Political commitment
Lack of technical guidance
11 vaccines are recommended by
WHO for infants in all countries
Vaccination schedule in Somalia
Relatively high price and lack of technical guidance results in a health gap
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Growing need for vaccines
• Globalization
• Migration
• Armed conflicts
• Population growth & urbanisation
• Climate change
• Chikungunya Dec 2013 - Mar 2015 (Americas)
• >1.3 million cases in 44 countries
• Ebola 2014 (W.Africa)
• 20,206 cases, 7905 deaths
• MERS-CoV 2012 - 2017 (Global)
• 2027 cases in 26 countries
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Highly Intensified
processing: sIPV
BMGF Grand Challenge
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Modular manufacturing facility
• Small footprint, very low CAPEX &
OPEX
• Commercial manufacturing at ‘lab
scale’
• 1000m2 micro-facility capable of
delivering 120M Vaccine doses / yr
Process Equipment & Integration
• High cell density, small footprint,
fixed-bed perfusion bioreactor incl in-
line concentration
• Chained Upstream and downstream
operations
• Isolator design for high containment
or biosafety cabinet design for
standard vaccines
Virus capture & purification
• High recovery chromatography
membranes for rapid, high-yield,
single step purification
Manufacturing process
• Vero / MRC-5 / 293 GMP cell lines
• Highly Intensified Process (HIP™)
incl: virus inactivation, formulation
• Analytical assays
• Documentation & Tech Transfer
Identify manufacturing platforms capable of delivering vaccines at a COGs of <$ 0.15 per dose
First target for low-cost manufacturing platform: Sabin-IPV
As the world moves toward complete polio
eradication, use of OPV (which can result in vaccine
associated paralytic poliomyelitis (VAPP) through
circulating vaccine-derived polioviruses (cVDPVs)
will be phased out and replaced by IPV.
Worlds need for IPV is growing rapidly beyond
todays available capacity
Current costs of IPV are at least 10-fold higher than
OPV
Urgent need to increase capacity and decrease costs
The world continues to struggle with IPV availability and supply at an affordable cost
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First target for low-cost manufacturing platform: Sabin-IPV
In December 2015, the World Health Organization (WHO)
requested that all countries conduct an inventory of their
poliovirus-containing materials.
Countries had to designate a National Authority for
Containment (NAC). The NAC is responsible for
implementing the containment plan in the country.
All facilities that continue to handle and store poliovirus
type 2 will require certification as a poliovirus-essential
facility (PEF). A PEF is a facility that maintains the ability to
work with and/or store infectious and potentially infectious
materials.
Urgent need for more affordable containment solutions
Implementation of WHO Global Action Plan (GAPIII) is costly, established vaccine
manufacturers may not be able to comply without disruption of supply
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Intensified, low-cost manufacturing platform: isolator-based micro-facility
Manufacturing process & Biological materialsGMP cell line (Vero / MRC-5 / 293) & virus seeds, manufacturing process, Analytical
assays, Inactivation
Equipment for process intensification & IntegrationHigh cell density, small footprint bioreactor, in-line single step purification
And small footprint containment (GAPIII) isolators
Platform consists of two parts
Equipment: Univercells
Nevoline™ using scale-X™ bioreactorsProcess: Batavia Biosciences
Highly Intensified Process (eg: HIP-PV®)
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Optimized cell line and production medium
High Cell Density/ fixed-bed Bioreactor
Affinity Purification Membranes
Integrated continuous process
High containment, low
footprint, low cost micro-
facility utilizing isolators
Pillar 3
Micro-facility technologies
Cabinet 1
• High density SU BR
• Inline clarification
Cabinet 2
• High capacity (affinity or
mixed mode) SU DSP
Cabinet 3
• Formalin
inactivation
✓
High density bioreactor linked
to single-step high capacity
capture chromo
Pillar 2
Intensification technologies
Process optimized WHO
Vero cell lines
Pillar 1
Expression system
$0.15 per
dose
IN
Cells &
Virus
OUT
Inactivated
bulk
Intensified, low cost manufacturing platform: isolator-based micro-facility
Industrial production at lab scale, process
intensification allowing isolator-based micro-facility
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Industrial manufacturing at lab scale in low cost “micro-facilities”
Miniaturization of equipment in a micro-facility
• Intensification of unit steps• Chaining into a continuous
process
1
2Micro-facility can be placed in BSL3 pod
micro-facility based production
• Footprint reduction enables isolators to be placed in container-sized BSL 3 pod
• Pod-based facility with a
simplified infrastructure
3
Delivers low CoGs
• Step change in manufacturing scale and yields
significantly reduces CoGs
Industrial production at lab scale
• Highly intensified process allows miniaturization
of commercial manufacturing
Rapid response to global threats• Factory operational in few months
• Can be implemented in new or existing
facilities
• Plug & Play system: can be rapidly
deployed in-country-for country manufacture
Broadly applicable to viral vaccines
High containment and safety
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HIP-PV® highly intensified, low-cost sIPV manufacturing process
• High cell density (30-40 million cells / mL ) and virus yields in upstream process using scale-X bioreactor
• High recovery (>90%) & purity (>98%) in downstream process
• Reduced process time (50% compared to standard microcarrier technologies) increasing facility capacity
• Simplified process & reduced handlings (eg: seed train almost entirely in scale-X bioreactor), reduced OPEX
• Parallel inactivation of up to 3 batches increasing facility capacity
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• Harvest yields are 5 to 6 times higher compared to microcarrier process
• DSP results in 1.5 to 3 times higher recoveries compared to microcarrier process* Bakker et al, Vaccine, 29, 2011
** Thomassen et al, Plos One, 8, 2013
High harvest yields and recoveries compared to microcarrier process
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H a rv e s t y ie ld s
Ha
rv
es
t y
ield
(DU
/mL
)
sP
V-1
sP
V-1
sP
V-2
sP
V-2
sP
V-3
sP
V-3
0
2 0 0
4 0 0
6 0 0
8 0 0
H a rv e s t y ie ld B a ta v ia
H a rv e s t y ie ld L ite ra tu re *
D o w n s tr e a m p r o c e s s r e c o v e r y
Re
co
ve
ry
(%)
sP
V-1
sP
V-1
sP
V-2
sP
V-2
sP
V-3
sP
V-3
0
2 0
4 0
6 0
8 0
O v e ra ll re c o v e ry B a ta v ia
O v e ra ll re c o v e ry L ite ra tu re * *
Kinetics of Inactivation comparable to traditional processes
0 1 0 2 0 3 0 4 0
0
2
4
6
8
1 0
L P 3 b , P V - 1 i n a c t i v a t i o n
T i m e [ H o u r s ]
PV
-1
KO
I (L
og
10
)
0 10 20 30 40 500
2
4
6
8
10
LP2, PV-2 inactivation
Time [Hours]P
V-2
KO
I (L
og10
)0 1 0 2 0 3 0 4 0 5 0
0
2
4
6
8
1 0
L P 2 , P V - 3 i n a c t i v a t i o n
T i m e [ H o u r s ]
PV
-3
KO
I (L
og
10
)
Time for complete inactivation is between 55 hrs and 75 hrs, Kinetics
of Inactivation (KoI) is comparable with reported literature data*
* Thomassen et al, Plos One, 8, 2013
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Conventional Isolator-based micro-
facility
Polio vaccine production Polio vaccine production
Breakthrough alternative for conventional processing
Stainless Steel facility
Batch-based
Lab-scale micro-facility
Chaining in a continuous process
GAPIII compliant
Footprint (m2) ~5,000 ~1,500
Capacity (doses/year) 50 million 50 million
CAPEX (million USD) 100-300 30
CoGs (USD/dose) 1.2-1.5 <0.30
Process time:
USP
DSP
4-5 wks
>3-4 days
3 wks
<24 hours
Reduction in footprint, CAPEX, OPEX and CoG’s
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Conventional
Isolator-based micro-
facility
Polio vaccine production
Polio vaccine production
Breakthrough alternative for conventional processing
Reduction in footprint, CAPEX, OPEX and CoG’s
PV infection & production
Preculture -1 Preculture -2 Preculture -3 Preculture -4 Preculture -5 Cell culture
Production BR
Preculture -1 Preculture -2 Preculture -3 Preculture -4 Cell culture & infection
Production BR
BR Harvest Clarification Concentration 1st chromatographystep
2nd chromatographystep
Buffer exchange Formulation Dilution & inactivation
Trypsinisation Trypsinisation
Harvest andConditioning/ online
TFF
Capture column Formulation Dilution & inactivationClarification
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Summary
Vaccine development & manufacturing costs and timelines remain critical in
assuring vaccine availability, high coverage and disease eradication
Emerging and re-emerging threats pose new demands on vaccine production
New process intensification technologies are being established that can
address these issues accelerating vaccine development, increasing capacity
and reducing costs
Polio containment
• In 2014 GSK discharged 45 liters of live type 3 poliovirus into the river (about 1013 pfu)
• In 2017 two workers in a vaccine plant in the Netherlands were exposed to wild type 2
poliovirus. One became infected and excreted virus for 29 days. The virus was detected
in sewage
Need of polio containment
Polio vaccine production needs to be contained
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System for confining polioviruses within a defined space
WHO Global Action Plan to minimize poliovirus facility-associated risk after type-specific Eradication of
wild polioviruses and sequential cessation of oral polio vaccine use (GAPIII).
What is poliovirus containment?
Global agreement:
WHA resolution 68.3:
The May 2015 resolution
urges countries to
implement GAPIII
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• 2002 assessment protocols and concept of biorisk management developed
• 2005 Polio biocontainment standards, draft GAPIII (2009)
• 2008 (2011) CWA 15793; Laboratory Biorisk Management
• 2014 revised GAPIII
• 2016 ISO Standard Biorisk Management
History of GAPIII in adopting a biorisk management philosophy
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The biorisk management approach recognized
as providing the highest level of assurance
Addresses both biosafety and biosecurity – “Biorisk”. A performance-orientated and risk-based approach
• Annex 2 - Essential facilities holding wild polioviruses
• Annex 3 - Essential facilities holding only OPV / Sabin
• Annex 2 - is identical to Annex 3 except for certain
facility containment-specific areas applying in Phase III
for containment of all wild poliovirus
• Annex 6 – Biorisk management standard for safe
handling of new samples potentially containing
poliovirus material in poliovirus-non-essential facilities
Annexes/elements: 3/16 elements has to do with equipment
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Initial GAPIII implementation timelines
2014 2015 2016 2017 2018 2019 2020 2021
Phase I: Global readiness coordination
Phase II:
Poliovirus type 2 containment periodPhase III:
Longterm poliovirus containment
Regional certification of
WPV eradication
OPV2 withdrawal
bOPVcessation
PV-essential
facilities
holding WPV IIIa: Final containment of all WPV
Inventory,
Destruction,
Preparation for containment
IIa: WPV2 containmentCtmt
certificationPV-essential
facilities
holding
OPV/Sabin
only (no
WPV)
IIIb: Containment of all Sabin
polioviruses IIb: OPV2/Sabin2 poliovirus containment
Inventory,
Destruction,
Preparation for containment Containment
certification
PV-non-
essential
facilities
Safe handling of new samples potentially containing PV material in non-essential
laboratories
Destruction,
Safe handling,
No storage Adopt safe measures
Global readiness
criteria met
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About us
Accelerating Biotechnology
Mission
“Batavia Biosciences actively develops
technologies in support of global health
initiatives and supports the biopharmaceutical
R&D industry in bringing new or improved
medicines to the market.”
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Batavia Biosciences
Expertise
• Viral & vector vaccines
• Bacterial vaccines
• Recombinant proteins
• Monoclonal antibodies
Research
Cell line generation, virus and
vector generation, candidate
selection, high quality
research material
Development
USP, DSP, Medium
Development, Analytical,
Technology Transfer
Manufacturing
Virus & Cell banking,
DS & DP Manufacturing, QC
Release, Stability Studies, IMPD
Support
Full-fledged service provider with a strong adaptability to the needs of our partners
Operations in Leiden, NL and Woburn, USA
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Global Health Partnerships
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More information: www.bataviabiosciences.com
Ahd Hamidi, Head Global Health Projects
+31 889950600