vaccine manufacturing facilities of the future - bptc · vaccine manufacturing facilities of the...
TRANSCRIPT
Howard L. Levine, Ph.D.Vaccines EuropeLondon, England
December 1 – 2, 2010
Vaccine ManufacturingFacilities of the Future
From Clone to Commercial®
Different technology platforms make it difficult to standardize facility design and equipment
• Unique facility and equipment may be necessary for each vaccine or class of vaccine
Many vaccines are typically low volume/high throughput products
• ≥ 1 million doses per year Live viral or bacterial vaccines
require special fill & finish facilities
No one facility will fit all products or processes
Challenges in the Production of Vaccines
From Clone to Commercial®
Live, attenuated Inactivated Subunit DNAToxoid
(Bacterial)Virus-likeparticle
Empirical Recombinant Purified RecombinantKilled,
metabolically active
VectorConjugate
(e.g., protein-polysaccharide)
Prime/boost combinations
Wide Range of Technologies Available for Vaccine Production
From Clone to Commercial®
Manufacturing Challenges
Many vaccines contain multiple strains or sub‐units• Influenza vaccine Contains antigens from 3 different strains Multiple upstream/downstream processes Single formulation and fill process
• Prevnar® (Pneumococcal CRM197 Conjugate Vaccines) 1 carrier protein (CRM197); 7‐15 serotypes of
polysaccharides Multiple conjugations Single formulation and fill process
Multiple cell lines used for vaccine productioni• Mammalian cell lines – VERO, MDCK, MRC5, BHK, CHO• Microbial cell lines – E. coli
From Clone to Commercial®
Large hard‐piped, stainless steel based facilities with stainless steel bioreactors
Very expensive to build and validate• Construction costs ≥$300 Million• Construction timelines 2‐5 years or more
Current Vaccine Manufacturing Facilities
Controlled environment, highly classified suites• Tightly controlled flow of people, materials, and equipment
Huge utilities for WFI, HVAC, Clean steam, CIP• Extensive piping, transfer panels,complex operations
Photos courtesy of Lonza Biologics
From Clone to Commercial®
Diversity of manufacturing facilities in the future
Complex supply chain and manufacturing Scale of upstream processes generally not
significant compared to other biopharmaceutical products
Vaccine manufacturing facilities traditionally require long lead times (3 – 5 years) and large capital investments
Unpredictability of demand necessitate flexible facilities Technology advancements
• Highly purified and characterized products• Cell culture replacing egg‐based technology• Introduction of disposable technology
From Clone to Commercial®
A Brief History of Disposable Systems in Biomanufacturing
1970sUse of flasks,
pipettes, filters,blood bags
1980sBags formedia,
harvest,buffer prep
1996Introduction of
WaveBioreactor
1998First
membraneadsorbers
2004First 250 Ldisposablebioreactor
2009First 2,000 Ldisposablebioreactor
Latest implementation of disposables include bioreactor harvest & clarification, cell concentration, downstream processing, and fill/finish operations
From Clone to Commercial®
Driving Forces for Single-Use Technologies
Improved return on capital• Reduced and deferred capital investment• Increased speed of deployment• Cost structure shifted to variable costs Significant reduction in capital equipment costs (>70%)
Reduced process equipment complexity• Process and product flexibility• Improved process control and portability
Reduced facility complexity and cost• Faster construction, commissioning, and launch• No change‐over cleaning/validation between strains/products• Significant reduction in facility/equipment validation
From Clone to Commercial®
Disposable Options Across Entire Manufacturing Flowpath
Recovery/Downstream Processing
Cell Culture
Media Prep/Storage
Buffer Prep/Storage
Formulation/FillDisposable Sensors
All conventional unit operations now have disposable format solutions
From Clone to Commercial®
Current Status of Disposable Systems
Almost all the unit operations and process components used in biomanufacturing can be replaced by disposables
The cost benefit, convenience, and flexibility of moving to disposables are well documented
More and more vendors are developing single use and disposable products
Companies are now moving to disposables for clinical and potentially commercial manufacturing
A completely disposable manufacturing flowpath should be possible in the foreseeable future
From Clone to Commercial®
GE Healthcare(Wave) Wave Bioreactor
Up to 1,000 L
Xcellerex SartoriusStedim
Thermo Fisher(Hyclone)
ATMI
XDRTM BioreactorUp to 2,000 L
Biostat® Culti‐bagUp to 1,000 L
Single‐use Bioreactor (S.U.B.)Up to 2,000 L
NucleoTM BioreactorUp to 1,000 L
Process Scale Disposable Bioreactors
From Clone to Commercial®
Stainless Steel vs. Disposable Bioreactors
Comparable cell growth and productivity
No cleaning or sterilization required
Fast turnaround
Minimal validation requirements
Increased flexibility and process portability
From Clone to Commercial®
Production of West Nile Vaccine
0.00E+00
5.00E+06
1.00E+07
1.50E+07
2.00E+07
2.50E+07
3.00E+07
3.50E+07
4.00E+07
4.50E+07
5.00E+07
0 48 96 144 192
Time in XDR-200 (h)
Cel
l Den
sity
80
100
Induce with 0.2 M CuSO4
Added Glucose
Added Gl
Added Antifoam and Glucose
Added Antifoam
Added Antifoam
Insect cell production in an XDR bioreactor
Data courtesy of Xcellerx
From Clone to Commercial®
Production of Rabies Vaccine
Vero cells grown on microcarriers in an ATMI bioreactor
Data courtesy of ATMI and sanofi pasteur
From Clone to Commercial®
Production of Influenza Vaccine
Photo and flowchart courtesy of Novavax
From Clone to Commercial®
Comparison of Disposable Bioreactors for Viral Production
0
20
40
60
80
100
120
DisposableBioreactor 1
DisposableBioreactor 2
DisposableBioreactor 3
Stainless SteelBioreactor
Relative Viral Produ
ction
Production of one viral serotype in three different disposable bioreactor systems
Ref: Chaudard J‐F, et al, BioPharm Supplement 2010
From Clone to Commercial®
Vaccine Facility Construction – A Tale of Three Technologies
Traditional egg‐based Mammalian Cell Culture Insect Cell Culture
Each fully‐integrated manufacturing facilities designed and estimated by the same US‐based engineering and construction firm in the time period 2004 – 2007
Ref: J. Trazzino, BIO2010
From Clone to Commercial®
sanofi pasteurEgg-based Facility
No bioreactors - 600K eggs/day100M doses/year140K square feet
$150MExisting site and infrastructure
NovartisMammalian Cell Culture Facility
Stainless steel bioreactors50M doses/year140K square feet
$600MNew site and infrastructure
NovavaxInsect Cell Culture Facility
Single-use bioreactor75M doses/year55K square feet
$40MNew site and infrastructure
Influenza Vaccine Facilities – A Tale of Three Technologies
Ref: J. Trazzino, BIO2010
From Clone to Commercial®
Time, yrs
0 1 2 3 4
Design
Construction
Commissioning
Qualification
Validation
Egg-Based
Process
InsectCell
Culture
Design
Construction
Commissioning
Qualification
Validation
Time Saved
Comparison of Project Duration
Ref: J. Trazzino, BIO2010
From Clone to Commercial®
Disposable Technologies Changing Manufacturing Facilities
Increased facility utilization by reducing change‐over time
Reduced fixed piping Reducing cleaning and
validation costs in multi‐product operations
Improved process portability Easier to manage and
implement process changes
Increased operational flexibility by minimizing or eliminating multi‐use equipment
Photo courtesy of Acceleron Pharma
From Clone to Commercial®
Next Generation Vaccine Manufacturing Facility
BPTC and Pharmadule have partnered to develop new modular biomanufacturing facilities
Standard design incorporates multi‐product capabilities, maximum flexibility, and disposable technologies
Designed for disposable bioreactors up to 2,000 L• Potential for multiple bioreactors per module
From Clone to Commercial®
Vaccine Manufacturing Facility Design Criteria and Assumptions
Designed to meet BSL‐2 requirements• Inoculum, bulk API filling under LAF protection in Class C• Class D for cell culture, downstream processing, dish
unloading, media and buffer preparation• Buffer preparation for final steps in Class D, LAF protected• Media and buffer storage in controlled, non‐classified areas
Batch duration 8 weeks including change over times• 4 weeks inoculum train, 2 weeks bioreactor, 1 week
purification, 1 week final purification 1 batch per month with overlap of inoculum preparation and cell
culture operations 12 batches per year multi‐product or 24 batches per year single‐
product
From Clone to Commercial®
Vaccine Manufacturing Modular Facility Layout
Process building only, connected to a spine with plant utilities Separate Mechanical and Process areas Segregation of Personnel and Material flow
From Clone to Commercial®
Model Plant – Single-use Floor 1
CapturingPurification
Cultivation
Media & BufferPreparation
Inoculum
Final Buffer ExchangeBulk API
Filling
Supply Corridor
Materials CorridorStaging Area
Personnel Corridor
Wash
From Clone to Commercial®
Cost Comparison – SS Bioreactor vs. Disposable Bioreactor
SS Bioreactor Disposable Bioreactor
Constrution Time 16 months 14 months
Process Area 6372 ft2 6781 ft2
Class C 1109 ft2 667 ft2
Class D 5231 ft2 3315 ft2
CNC 0 ft2 2745 ft2
Total Area 12,153 ft2 13,014 ft2
Piping Length 2854 ft 886 ft
Process Equipment 4.0 m€ 3.0 m€
Total Capital Cost 17,3 m€ 15 m€
From Clone to Commercial®
Economics of Stainless Steel vs. Disposables
Start‐up Costs Operating Costs
Ref: Galliher, 2010; Foulon, et al. 2010
From Clone to Commercial®
Thank you!
BioProcess Technology Consultants, Inc.
12 Gill Street, Suite 5450
Woburn, MA 01801
781.281.2703
www.bioprocessconsultants.com