A unique full-service biotech partner for innovation and manufacturing of GMO2/BSL2 sterile liquid and lyophilized products
BAVARIAN NORDICTHE COMPLEX MADE SIMPLE
CDMO SERVICES FOCUSED ON BRINGING VACCINES TO MARKET
CDMO SERVICES
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Development
• Process development• Formulation development• Analytical development
Manufacturing of live and inactivated viruses
• Master seed virus• Working seed virus
Drug substance
• Pilot plant scale• Clinical and Commercial scale
Current Fill & Finish Services
• Clinical trial and Small scale manufacturing
Support services
• Quality• Project Management
2020 Fill & Finish Services
• Large scale manufacturing and Lyophilization• Integrated label and packaging line• Serialization
Full-Service offer
Bavarian Nordic4
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20-25
26 Roadmap to full CDMO services for live vaccines
THE COMPLEX MADE SIMPLE CONTENT
CDMO SERVICES
A globally integrated biotechnology company
Bavarian Nordic is focused on in-house executed research, development, manufacturing and marketing of innovative and safer vaccines against cancer and infectious diseases for which the unmet medical need is high and for which we can harness the power of the immune system to induce a response.
Based on this in-depth experience we are now entering the CDMO market, making the complex simple for you.
As innovators and developers of live virus vaccines, our combination of 25 years expertise and state-of-the-art facility, we can guide and accelerate your biological therapeutics from development to commercial and beyond.
Focused on bringing vaccines to market
Highly efficient and flexible BSL2/GMO2 classified facility
• Cell banking• Inoculum preparation• Cell culture• Harvest and recovery• Purification• Clinical trial and small scale fill and finish
Expanding dedicated CDMO capacity
Isolator technology
Large-scale lyophilization
High-speed labeling and packaging
BAVARIAN NORDIC LEADING VACCINES FOCUSED BIOTECH COMPANY
Our vaccine platform takes a modular approach to live virus vaccine development and is based on the use of different types of poxviruses
• These viruses can be used in various combinations for both the prime and booster applications
OUR VACCINE PLATFORM IS APPLICABLE TO DIFFERENT THERAPEUTIC AREAS
Broad platform with an approved product
• Applicable to cancer and infectious diseases
• Can stimulate broad and sustained immune responses
• Well tolerated in clinical trials
Based on large viruses which allows for larger DNA packag-ing capacity
Ability to encode multiple targets for specific diseases
Bavarian Nordic has built its foundation around two poxviral-based vaccine platform technologies
• Modified Vaccinia Ankara – Bavarian Nordic (MVA-BN)• Vaccinia-Fowlpox-TRICOM (VF-TRICOM)
4 BAVARIAN NORDIC BAVARIAN NORDIC 5
Bavarian Nordic
Revenue generating; strong cash position
Excellent track history in government and pharma collaborations
Approved discovery platform
Differentiated pipeline in cancer and infectious diseases
Fully integrated R&D & manufacturing
NEW FILL & FINISH FACILITY BY 2020
CDMO SERVICES
Speaking as one biotech company to another, we appreciate the virtues of product development and manufacturing.
With our combination of 25 years expertise and state-of-the-art facility, we can guide and accelerate your biological therapeutics from pre-clinical to commercial stage and beyond while delivering the highest quality and reliable sterile products that improve the health and quality of life for children and adults.
By expanding our clinical and small small commercial capa-bilities, including a new fill and finish facility with dedicated capacity for our customers, we will support you in bringing your valuable products to your patients in a timely manner.
BAVARIAN NORDIC CDMO SERVICESA UNIQUE FULL-SERVICE BIOTECH PARTNER FOCUSED ON BRINGING VACCINES TO MARKET
6 BAVARIAN NORDIC
Full-Service offer in our GMO2/BSL2 facility meeting all cGMP requirements
BAVARIAN NORDIC 7
Fill & Finish services for Drug ProductClinical trial and Small scale manufacturingLarge scale manufacturing, including lyophilization and integrated packaging line, by 2020Page 16-17 + 20-25
Development
Process Process development Formulation developmentAnalytical developmentPage 8-13
Manufacturing of live and inactivated virusesMaster seed virus Working seed virusPage 14
Drug substancePilot plant scaleClinical and Commercial scalePage 15
Support servicesQualityProject ManagementPage 18-19
CDMO SERVICES
PROCESS DEVELOPMENT FORMULATION DEVELOPMENT ANALYTICAL DEVELOPMENT | DEVELOPMENT 98 DEVELOPMENT | PROCESS DEVELOPMENT FORMULATION DEVELOPMENT ANALYTICAL DEVELOPMENT
Full-Service offer in our GMO2/BSL2 facility meeting all cGMP requirements
Upstream capabilities and technology
• Batch, fed-batch, or perfusion process development
• Media screening & optimization
• Seed train design
• Inoculation optimization
• Harvest development & optimization
Upstream technology for
Suspension cell cultures:
• Bioreactors• Wave bioreactor• Glass• Single-use
Adherent cell cultures:
• Roller bottles• iCellis bioreactor• Microcarriers in
bioreactors
Downstream capabilities and technology
• Design, develop and optimize.
• Clearance (Depth filtration, batch centrifugation, continuous centrifugation)
• Purification development• Tangential Flow Filtration
(TFF)• Virus sucrose gradient
ultracentrifugation
Characterization
• Process characterization• Upstream• Downstream
• Particle size distribution by• Nanoparticle Tracking
Analysis (NTA)• Micro-Flow Imaging
(MFI)
• Computer Fluid Dynamics (CFD) analytics
Pilot scale
• BSL2/GMO2 pilot facility (non-GMP)
• Up to 50L
Scale up capabilities
• From upstream/downstream 1L up to 250L
DEVELOPMENT PROCESS DEVELOPMENT SERVICE
At Bavarian Nordic, we have in-depth expertise in all aspects of upstream and downstream development and improvement of the drug/product manufacturing process. This will help you facilitate and accelerate your preclinical drug development process.
We will support you in the set-up of well-defined, scalable and reproducible processes needed to make successful therapeutic products in a commercially viable and regula-tory compliant way.
WE HAVE EXTENSIVE EXPERIENCE IN:
• CRITICAL PARAMETER DEFINITION BY DESIGN OF EXPERIMENTS (DOE)
• PROCESS VALIDATION SUPPORT
• PROCESS DEFINITION, OPTIMIZATION & SCALE-UP
CDMO SERVICES
1110 DEVELOPMENT | PROCESS DEVELOPMENT FORMULATION DEVELOPMENT ANALYTICAL DEVELOPMENT
Full-Service offer in our GMO2/BSL2 facility meeting all cGMP requirements
Formulation development
• Screening of excipients• Accelerated stability
studies• Homogeneity and mixing
studies• Filtration• Computer Fluid Dynamics
(CFD)analytics
Primary packaging compatibility testing
• Extractable/leachable testing
• Container Closure Integrity Testing
Science is the foundation of formulation. And our people can make the difference.
A good formulation must be manufacturable, chemically and physically stable throughout the manufacturing pro-cess and product shelf life, and bioavailable. In addition, many quality standards and special requirements must be met to ensure the efficacy and safety of the product and, as well as speed and cost-effectiveness of development and the final product.
Because of the complex technical challenges our scientists encounter during formulation development, it is important to use an effective methodology. Design of Experiments (DOE) and statistical analyses are applied to formulation development and are useful in process optimization and process validation.
PROCESS DEVELOPMENT FORMULATION DEVELOPMENT ANALYTICAL DEVELOPMENT | DEVELOPMENT 11
CDMO SERVICES
DEVELOPMENT FORMULATION DEVELOPMENT SERVICE
CDMO SERVICES
QC support
• Production sample and raw material sample reception, registration and aliquoting
• Sample distribution, internally as well as externally
• Setting specifications for raw materials
• Preparation of internal and external Certificates of Analysis
• AQL for filling operations
• Maintenance of stability overview for samples, distribution of samples for testing and collection and report-ing results
• Sample Manager
PROCESS DEVELOPMENT FORMULATION DEVELOPMENT ANALYTICAL DEVELOPMENT | DEVELOPMENT 1312 DEVELOPMENT | PROCESS DEVELOPMENT FORMULATION DEVELOPMENT ANALYTICAL DEVELOPMENT
Full-Service offer in our GMO2/BSL2 facility meeting all cGMP requirements
DEVELOPMENT ANALYTICAL DEVELOPMENT SERVICE
Analytical method develop ment, validation and transfer are key elements of any phar-maceutical development program.
We can offer our expertise to support the analytical development, transfer, validation and quality control release testing needed to get your product to clinic or market.
QC Chemistry
• BCA for quantification of protein
• Quantitative residual Benzonase ELISA
• Qualitative Benzonase ELISA
• Gentamycin • pH and conductivity
measurements• Appearance testing• Extractable Volume• Density measurements• Qualitative magnesium
test• Gas detector tubes• Bioprofile analysis –
Raw materials • Cell detachment test• External tests
• Host cell Protein• Residual Trypsin• Osmolality
Microbiology
• Total Viable Count (TVC) on water samples
• Total Viable Aerobic Count (TVAC)
• Identification of micro organisms
• Growth Promotion Test (GPT)
• Test for gentamicin content – Cylinder plate, Turbidimetric method
• Incubation and reading of samples from envi-ronmental monitoring in Bulk Production
• Cell count analysis• Endotoxin tests • Extraneous agents
in vitro
External testing
• Avian Leucosis Virus (ALV)
• Extraneous agents in vitro (2. and 3. passage)
• Test for Sterility• Bioburden• Test for Mycobacterium• Test for Mycoplasma• Extraneous agents
in vivo• Adult mice• Eggs• Guinea pigs• Host cell Protein• Residual Trypsin• Osmolality
Molecular biology
• Identity by PCR• Genetic purity• Host cell DNA
(CEF DNA quantifica-tion)
• Q-PERT• Virus titer by FACS• Co-expression of
Transgenes by FACS• Transgene expression
by Western Blot• Transgene expression
by RT-PCR
Clinical Analysis
Analysis of immune responses (humoral and cellular) in patients by:
• PRNT (plaque reduction neutralization) (Vaccin-ia and RSV)
• ELISA (Vaccinia and RSV)
• ELISPOT (T-cell/ B-cell) (Vaccinia and RSV)
• ICS (intracellular cyto-kine staining) (RSV)
Characterization
• Quantification of viral genomes (Vaccina/MVA copy numbers)
• Restriction Site Analysis of the Viral Genome
CDMO SERVICES
Cell Culture based on
• Adherent and suspension cell platforms• Avian cell lines – e.g. EB66• Chicken Embryo Fibroblast (CEF) cells
Process technology
• Bioreactors• Wave bioreactors up to 300L (6 x 50L bags)• Single-use Bioreactors up to 250L
• Roller bottles• Up to 450 bottles
Recovery & purification
• Harvest vessel
• Clearance • Depth filtration• Batch centrifugation• Continuous centrifugation
• Purification• Tangential Flow Filtration (TFF)• Sucrose gradient ultracentrifugation
• cGMP • BSL2/GMO2• Clinical and commercial scale• Master seed virus/Working seed virus
generation and storage• Stability testing and storage
• cGMP • BSL2/GMO2• Clinical and commercial scale• Stability testing and storage• Drug substance storage -20ºC, -50ºC, -80CºC
14 VIRUS MANUFACTURING | MASTER SEED VIRUS WORKING SEED VIRUS PILOT PLANT SCALE CLINICAL AND COMMERCIAL SCALE | DRUG SUBSTANCE 15
Full-Service offer in our GMO2/BSL2 facility meeting all cGMP requirements
MANUFACTURING OF LIVE AND INACTIVATED VIRUSES· MASTER SEED VIRUS · WORKING SEED VIRUS
Establishing a high-quality Master and Working Cell Bank is a key step in securing material for clinical and com-mercial supply.
Our virus seed banking processes and the BSL2 facility we use to manufacture your virus seed stocks are fully GMP compliant and offer a high quality, stable and fully traceable starting material for GMP manufacturing of clinical and commercial products.
DRUG SUBSTANCE· PILOT PLANT SCALE· CLINICAL AND COMMERCIAL SCALE
CDMO SERVICES
Inspection
• Manual inspection• In compliance
with FDA and EMA regulations
• Inspection booths with black-and-white inspection backgrounds
• Operator qualification via performance-based assessments
Vial labeling and packaging
• Manual• Semi-automated for
small scale commercial volumes
Clinical & small scale manufacturing
• Formulation• Filtration• Aseptic filling• Visual inspection• Labeling• Packaging• Stability testing
16 CURRENT FILL & FINISH SERVICES | CLINICAL TRIAL AND SMALL SCALE MANUFACTURING CLINICAL TRIAL AND SMALL SCALE MANUFACTURING | CURRENT FILL & FINISH SERVICES 17
Filling line
• Automated filling and capping
• Closed RABS system• Containers: DIN2R vials
RTU and others• Batch size: up to
10,000 vials• Line output: 1,000 vials
per hour• Automated IPC• Peristaltic pumps• Single-use product
contact parts• VHP inactivation
procedure
Full-Service offer in our GMO2/BSL2 facility meeting all cGMP requirements
CLINICAL TRIAL AND SMALL SCALE MANUFACTURING AREA
FILL & FINISH SERVICES TODAY· CLINICAL TRIAL · SMALL SCALE MANUFACTURING
Bavarian Nordic currently offers biologics contract manu-facturing using innovative filling line technologies that are specifically designed to protect your biologic’s integrity and optimize yield of costly drug product.
This is a BSL2/GMO2 multiproduct facility able to handle live vaccines.
With a wealth of experience dealing with biologics, our scientists provide expertise across all areas of parenteral formulation and sterile manufacturing.
CDMO SERVICES
CLINICAL TRIAL AND SMALL SCALE
FILLING LINE
VISUAL INSPECTION, LABELING AND PACKAGING
Qualified persons
• Manufacturing authori-zation according to §39
• Facilities in compliance with EU and US GMP
• 4 Qualified Persons
Deviations and CAPA
• SharePoint platform• Designed and qualified
to meet 21 CFR Part 11• Access control• Audit trail• E-signature
• Minor, Major deviations• CAPAs • Automatic numbering• Personal and Depart-
ment Dashboards• Reports
Change Control System
• SharePoint platform• Designed and qualified
to meet 21 CFR Part 11• Access control• Audit trail• E-signature
• Cat. 1, 2 & 3 CRs• Risk assessment
• Automatic numbering• Personal and Location
Dashboards• Reports
Quality Documents System
• SharePoint platform• Designed and qualified
to meet 21 CFR Part 11• Access control• Audit trail• E-signature
• Contains • Procedures• Validation/Qualifi-
cation docs.• Specifications• Various studies,
trends, technical reports
• Includes SOP training• Access to pdf version of
document• Automatic publishing
on effective date• System notification to
relevant people at approval & obsoletion
Regulatory services
Bavarian Nordic can offer CMC support throughout product development and support the customers’ regulatory filings; CTA, IND, BLA/NDA and MAA
Bavarian Nordic can also offer to author Module 3 (CMC) for the process steps that are taking place at Bavarian Nordic.
18 SUPPORT SERVICES | QUALITY PROJECT MANAGEMENT QUALITY PROJECT MANAGEMENT | SUPPORT SERVICES 19
Full-Service offer in our GMO2/BSL2 facility meeting all cGMP requirements
• Bavarain Nordic believes in the importance of a dedi cated project manager, who will follow projects from early development and through to final release and delivery.
• Mirroring customer´s project struture ensures clear and swift communication between key project members, unless customer prefer Bavarian Nordic project manager to be “one-point-of-contact”
• Bavarian Nordic project managers provide close and reli-able support for customers, as this is vital to any successful collaboration
• Strong product planning from idea conception to market launch – in close cooperation with the customers
• Product life cycle strategies are developed and continu-ously monitored throughout the project
SUPPORT SERVICESQUALITY
SUPPORT SERVICESPROJECT MANAGEMENT
CDMO SERVICES
Full-Service offer in our GMO2/BSL2 facility meeting all cGMP requirements
FILL & FINISH SERVICES LARGE SCALE MANUFACTURING AND LYOPHILIZATION BY 2020
Storage capabilities
Temperature monitored storage capabilities for:
• Room temperature• Cold storage: 2-8ºC• Freezer storage -
outside F&F facility:• -20ºC, -50ºC, -80ºC
Formulation• T-controlled single-use
mixing systems using aseptic connections
• Optional: Open hand-ling within Grade A formulation isolator
Vial filling and closing
• Bosch filling line with isolator
• BSL 2/GMO2• Up to 400 units/minute• Annual capacity up to:
• 40M units for filling
• 10M units for filling and lyo
• Vial sizes: DIN2R and others
• 100% fill-weight checker
• Gas blanketing during filling
• Peristaltic pump mechanism
• Capping line in cRABS area
• Single-use product contact parts
LARGE SCALE MANUFACTURING AND LYOPHILIZATION | 2020 FILL & FINISH SERVICES 21
CDMO SERVICES
LARGE SCALE MANU FACTURING AND LYOPHILIZATION BY 2020
20 2020 FILL & FINISH SERVICES | LARGE SCALE MANUFACTURING AND LYOPHILIZATION
Terminal sterilization
• Getinge autoclave• Steam Sterilization
(air over pressure) • 90.000 DIN2R vial
per load
VIAL WASHING
VIAL DEPYROGENAZTION
VIAL FILLING
INSPECTION
PACKAGING
EXPANSION AREA
VIAL STOPPER AND CAPPING
LYOPHILIZATON Lyophillization
• 40m2 IMA lyophilizer• 15 shelf unit• Fully automated load-
ing/unloading within isolator protection
• Liquid nitrogen cooled• Tempris product tem-
perature monitoring system
• 180.000 DIN2R vial per load
CDMO SERVICES
OPERATIONAL 2020 CLINICAL AND COMMERCIAL SCALE• Fill & finish
• Live vaccines
• Multi product facility
• Isolator technology
• BSL2 – GMO2
• Lyophilization
• FDA “Type C” reviewed
design and operation
• Integrated packaging line
• Serialization
22 2020 FILL & FINISH SERVICES | LARGE SCALE MANUFACTURING AND LYOPHILIZATION LARGE SCALE MANUFACTURING AND LYOPHILIZATION | 2020 FILL & FINISH SERVICES 23
CDMO SERVICES
Vial Inspection
• Manual• Inspection booths with black-and-white
inspection backgrounds• Operator qualification via performance-based assess-
ments
• Semi-Automated• Seidenader semi-
automated inspection machines• Liquid and lyophilized vials• Vial sizes: DIN2R vials and others
24 2020 FILL & FINISH SERVICES | LARGE SCALE MANUFACTURING ... INTEGRATED LABEL AND PACKAGING LINE, SERIALIZATION
Full-Service offer in our GMO2/BSL2 facility meeting all cGMP requirements
FILL & FINISH SERVICES BY 2020· INSPECTION · LABELING · PACKAGING · SERIALIZATION
Integrated label and packaging line
Bosch Integrated label and packaging line for packaging of DIN 2R vials in multidose packs
• Pre-folded leaflet or booklet dispenser
• Cartoner• Carton erecting• Inlet insertion• Laser print for human readable text and 2D matrix• Hot melt glue sealing
– (Line is ready for tamper evident label applicator)• Up to 80 carton per minute
• High speed wrap around Labeling machine• >400 vials per minute • Laser print of batch data
• Pick and place inlay loader• Erecting and loading of Cardboard Inlay• Line build for 20 vial inlays• Inlay constructed to prevent glass to glass contact• Multiple product vacuum gripper• Up to 100 picking cycles per minute
Serialization and aggregation
Line is built with full serialization and aggregation capabilities
• Case packer• Automatic case
aggregation• Serialization data
capture
• Pallet aggregation• Serialization data
capture
• Potential batch functionalities1. No serialization2. Serialization no aggregation3. Serialization and aggregation to case level4. Serialization and aggregation to case and pallet level
• Suitable for multiple serial number formats
• Communication interface with MA holder can be set up to suit scale of production.
LARGE SCALE MANUFACTURING ... INTEGRATED LABEL AND PACKAGING LINE, SERIALIZATION | 2020 FILL & FINISH SERVICES 25
CDMO SERVICES
26 ROADMAP TO FULL CDMO
Roadmap to full CDMO services for live vaccines
ROADMAP TO FULL CDMOSERVICES FOR LIVE VACCINES
2019
LARGE SCALE COMMERCIAL FACILITY
MULTI PRODUCT FACILITY
ISOLATOR TECHNOLOGY
BSL2
LYOPHILIZATION
PROCESS DEVELOPMENT & TECH TRANSFER
INTERNAL PRODUCT DEVELOPMENT
EXPERIENCE WITH TRANSFER FROM AND TO EXTERNAL SITES.
EXTENSIVE EXPERIENCE WORKING WITH EXTERNAL PARTNERS IN BRINGING EXTERNAL PROGRAMS TO CLINIC PHASE
BSL2 PILOT PLANT
CGMP FACILITIES — BSL2/GMO2
SINGLE — USE BIOREACTORS + MULTI PRODUCT FACILITY USING AVIAN CELL LINES AND CHICK EMBRYO FIBROPLAST (CEF) CELLS GROWN IN ROLLER BOTTLES AND WAVE BAGS
2020
2004
1994
MSVMANUFACTURING
WSVMANUFACTURING
BDSMANUFACTURING
CLINICAL TRIALMANUFACTURING
SMALL SCALEMANUFACTURING
DISCOVERY
RESEARCH
DEVELOPMENT
MULTI PRODUCT FACILITY USING AVIAN CELL LINES AND CHICK EMBRYO FIBROPLAST (CEF) CELLS GROWN IN ROLLER BOTTLES AND WAVE BAGS
HIGH SPEED PACKAGING LINE AND SERIALIZATION
FILL & FINISH FOR DRUG PRODUCT
ROADMAP TO FULL CDMO 27
Bavarian Nordic is a global fully vertically integrated biotechnology company focused on the in-house executed research, development, manufacturing and marketing of innovative and safer vaccines against cancer and infectious diseases for which the unmet medical need is high and for which we can harness the power of the immune system to induce a response.
As innovators and developers of live virus vaccines, we are fully aware of the complex challenges and risks associated with bringing a product to market under the strictest of regulations. Our combination of expertise, state-of-the-art facility and technology, can guide and
accelerate your biological therapeutics from development to commercial stage and beyond while delivering the highest quality and reliable sterile products that improve the health and quality of life for children and adults.
You can rely on us to make the complex simple
• Founded 1994, IPO 1998• Listed on NASDAQ OMX Copenhagen: BAVA• Employees: +400 • First product (MVA-BN as smallpox vaccine)
approved in 2013
Bavarian NordicHejreskovvej 10A
DK-3490 Kvistgaard
Denmark
Bavarian Nordic 3025 Carrington Mill Boulevard
Morrisville NC 27560
USA
Bavarian Nordic Fraunhoferstrasse 13
D-82152 Martinsried
Germany
