Vaccine manufacturing facilities of the future - BPTC · Vaccine Manufacturing Facilities of the Future. ... • No change‐over cleaning/validation between strains/products

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


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


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


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


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


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


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


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


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


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


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


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


Production of Rabies Vaccine

Vero cells grown on microcarriers in an ATMI bioreactor

Data courtesy of ATMI and sanofi pasteur


Production of Influenza Vaccine

Photo and flowchart courtesy of Novavax


Comparison of Disposable Bioreactors for Viral Production

0

20

40

60

80

100

120

DisposableBioreactor 1



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


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


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



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



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


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


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


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


Model Plant – Single-use Floor 1

CapturingPurification

Cultivation

Media & BufferPreparation

Inoculum

Final Buffer ExchangeBulk API

Filling

Supply Corridor

Materials CorridorStaging Area

Personnel Corridor

Wash


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€


Economics of Stainless Steel vs. Disposables

Start‐up Costs Operating Costs

Ref: Galliher, 2010; Foulon, et al. 2010


Thank you!

BioProcess Technology Consultants, Inc.

12 Gill Street, Suite 5450

Woburn, MA 01801

781.281.2703

[email protected]

www.bioprocessconsultants.com

Documents

Vaccine manufacturing facilities of the future - BPTC · Vaccine Manufacturing Facilities of the Future. ... • No change‐over cleaning/validation between strains/products