Vaccine Manufacturing Facilities of the Future. Howard L. Levine, Ph.D. Vaccines Europe London, England December 1 2, 2010

Transcription

1 Vaccine Manufacturing Facilities of the Future Howard L. Levine, Ph.D. Vaccines Europe London, England December 1 2, 2010

2 Challenges in the Production of Vaccines 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

3 Wide Range of Technologies Available for Vaccine Production Toxoid (Bacterial) Live, attenuated Virus-like particle Inactivated Subunit DNA Killed, Empirical Recombinant metabolically Purified Recombinant active Vector Conjugate (e.g., proteinpolysaccharide) Prime/boost combinations

4 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

5 Current Vaccine Manufacturing Facilities 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 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

6 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

7 A Brief History of Disposable Systems in Biomanufacturing 1970s Use of flasks, pipettes, filters, blood bags 1996 Introduction of Wave Bioreactor 2004 First 250 L disposable bioreactor 1980s Bags for media, harvest, buffer prep 1998 First membrane adsorbers 2009 First 2,000 L disposable bioreactor Latest implementation of disposables include bioreactor harvest & clarification, cell concentration, downstream processing, and fill/finish operations

8 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

9 Disposable Options Across Entire Manufacturing Flowpath Cell Culture Recovery/ Downstream Processing Disposable Sensors Formulation/ Fill Media Prep/ Storage Buffer Prep/ Storage All conventional unit operations now have disposable format solutions

10 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

11 Process Scale Disposable Bioreactors Xcellerex Sartorius Stedim Thermo Fisher (Hyclone) ATMI XDR TM Bioreactor Up to 2,000 L Biostat Culti bag Up to 1,000 L GE Healthcare (Wave) Single use Bioreactor (S.U.B.) Up to 2,000 L Nucleo TM Bioreactor Up to 1,000 L Wave Bioreactor Up to 1,000 L

12 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

13 Production of West Nile Vaccine 5.00E E E+07 Added Gl Cell Density 3.50E E E E+07 Added Antifoam and Glucose Added Antifoam 1.50E+07 Added Glucose 1.00E E E+00 Induce with 0.2 M CuSO 4 Added Antifoam Time in XDR-200 (h) Insect cell production in an XDR bioreactor Data courtesy of Xcellerx

14 Production of Rabies Vaccine Vero cells grown on microcarriers in an ATMI bioreactor Data courtesy of ATMI and sanofi pasteur

15 Production of Influenza Vaccine Photo and flowchart courtesy of Novavax

16 Comparison of Disposable Bioreactors for Viral Production Relative Viral Production Disposable Bioreactor 1 Disposable Bioreactor 2 Disposable Bioreactor 3 Stainless Steel Bioreactor Production of one viral serotype in three different disposable bioreactor systems Ref: Chaudard J F, et al, BioPharm Supplement 2010

17 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 Ref: J. Trazzino, BIO2010

18 Influenza Vaccine Facilities A Tale of Three Technologies sanofi pasteur Egg-based Facility No bioreactors - 600K eggs/day 100M doses/year 140K square feet $150M Existing site and infrastructure Novartis Mammalian Cell Culture Facility Stainless steel bioreactors 50M doses/year 140K square feet $600M New site and infrastructure Novavax Insect Cell Culture Facility Single-use bioreactor 75M doses/year 55K square feet $40M New site and infrastructure Ref: J. Trazzino, BIO2010

19 Comparison of Project Duration Design Egg- Based Process Construction Commissioning Qualification Validation Design Construction Insect Cell Culture Commissioning Qualification Validation Time Saved Time, yrs Ref: J. Trazzino, BIO2010

20 Disposable Technologies Changing Manufacturing Facilities Increased facility utilization by reducing change over time Reduced fixed piping Reducing cleaning and validation costs in multiproduct 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

21 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

22 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 singleproduct

23 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

24 Model Plant Single-use Floor 1 Supply Corridor Inoculum Wash Media & Buffer Preparation Cultivation Materials Corridor Staging Area Final Buffer Exchange Bulk API Filling Purification Personnel Corridor Capturing

25 Cost Comparison SS Bioreactor vs. Disposable Bioreactor SS Bioreactor Disposable Bioreactor Constrution Time 16 months 14 months Process Area 6372 ft ft 2 Class C 1109 ft ft 2 Class D 5231 ft ft 2 CNC 0 ft ft 2 Total Area 12,153 ft 2 13,014 ft 2 Piping Length 2854 ft 886 ft Process Equipment 4.0 m 3.0 m Total Capital Cost 17,3 m 15 m

26 Economics of Stainless Steel vs. Disposables Start up Costs Operating Costs Ref: Galliher, 2010; Foulon, et al From Clone to Commercial

27 Thank you! BioProcess Technology Consultants, Inc. 12 Gill Street, Suite 5450 Woburn, MA