Cell culture based vaccine production :Engineering Bottlenecks

Etienne Malhaize,

Director of Technical Service – Process Biotech.

Cell culture based vaccine production :Engineering Bottlenecks

Etienne Malhaize,

Director of Technical Service – Process Biotech.

NAE/IOMConference April 10 th , Vaccine production : Potential Engineering Approach to a Pandemic

AgendaAgenda

GSK Biologicals Flu approach Introduction to vaccine manufacturing process

Engineering approach to a pandemic : – The request :

• « Please, build a 100 MM dose/y Flu Pandemic facility… »

– The context : • Cell culture technologies • GMP and Biosafety Level 3 (BL3)• Qualification

– The standard timing for a new vaccine facility

– The opportunities to reduce timing

Product streams

• Classical flu vaccine: egg derived

• Classical flu vaccine: adjuvanted formulation

• Tissue Culture

• Pandemic

Flu approach in GSK BiologicalFlu approach in GSK Biological

Hamilton

Rixensart

Shanghai

Singapore

Dresden

Egypt

Gödöllö Moscow

St. Amand les Eaux

Nashik

Brazil

Marietta

(Asia Pac)

Wavre

Alliances

JV’s

Affiliates

QuebecMontreal

GSK BiologicalsGSK Biologicals

Global Industrial Operations NetworkGlobal Industrial Operations Network

Improved Flu Vaccine for elderly

using adjuvant

Build egg-based critical mass: • Dresden (60 m doses) • ID Biomedical (75 m doses)

Introducing a new cell-culture based

production (~2010)

GSK Positioned to be a Flu Vaccine LeaderGSK Positioned to be a Flu Vaccine Leader

Extensive preparationsfor pandemic flu

Developing new delivery systems

IntroductionIntroduction

Typical vaccine production process :Typical vaccine production process :

PACKAGING

FORMULATIONBULK

Antigen 1

Antigen 2

Antigen 3

Adjuvant

FILLING

The request The request

« Please, build a 100 MM dose/y facility for Flu-pandemic »« Please, build a 100 MM dose/y facility for Flu-pandemic »

Question 1  – What does a « dose » mean ?  – Is it 100 µg , 10µg, 1 µg…?

Nobody knows…and unfortunately, first clinical trials on H5N1 demonstrate poor immune response compared with classical seasonal Flu-vaccine.

Question 2– How Engineering can help ?

Design and build Flu facilities as « flexible » as possible for both

Antigen and Adjuvant Bulk production.

– modular design approach

Learning 1 :Learning 1 : We need to buildbefore clinical results are completed

Risk : Potential impact: -Capacities-Budget-Timing

µ-carriers Cells are anchorage dependent

and are growing on µ -beads

High antigen yields (Y=5) Typical size : 1.000 L

Majors challenges– Shear stress and mixing– Sub passages – Continuous fresh culture

media perfusion (often 3 days)

Free cell suspension Cells are growing on a free suspension

Low antigen yields (Y=1) Typical size : 5.000 L

Major challenges– Bigger volumes – Longer cell culture lead time.

The context : The context :

Cell culture : µ-carriers or free suspension ? Cell culture : µ-carriers or free suspension ?

Question 3 : « What will be the impact of cell culture technology on design ?»

The context : The context :

Impact of cell culture on equipment and facility design Impact of cell culture on equipment and facility design

µ-carriers cell culture Free cell suspension culture

Tank(CIP/SIP)1x 3000L

MediaTank(in use)1x 3000L

Footprint unit in Media Prep. Area

Fermented1x1000L

Fermented1x1000L

Fermented=Harvest tank1x5000L

Harvest tank1x3000L

Footprint unit in Cell Culture room

MediaTank(in use or in SIP/CIP)1x 1000L

MediaTank(in use or in SIP/CIP)1x 5000L

µ-carriers Free cell suspension

6Footprint (in unit for one train) 4

6

6

~4mCeiling height(in meters)

~3m

~6m

~6m

Learning 2 :Learning 2 : Depending on the cell culture technology , the equipment and facility design can dramatically change…then, build very flexible !

The context :The context :

Impact of cell culture on equipment and facility designImpact of cell culture on equipment and facility design

Media Prep. Area

Cell Culture room

2 x 3000LMedia tank (by train)Fermented (by train)Harvest tank (by train)

1 x 1000L1x1000L + 1x5000L1x1000L + 1x5000L

1 x 3000L NA

µ-carriers Free cell suspension

From design…

Fermenters(1000L)

10 months

Fermenters(5000L)

10 to 14 (*) months

(*) Special facility construction

design if >5000 L

...to Delivery

The context :The context : Impact of cell culture on equipment and facility designImpact of cell culture on equipment and facility design

Learning 3 :Learning 3 :

Anticipate purchasing of long lead items (strong specifications and long term partnership with critical suppliers required…)

Learning 4:Learning 4:

Introduce new technologies (e.g. disposables)

The context : The context :

GMP and Biosafety in BL3GMP and Biosafety in BL3

Personnel Flow

Clean Equipment/Material FlowWaste Flow

Process Flow

MALIN

MALOUT

PAL1

PAL3

PAL2

Typical BSL 3 process viral contained area

Sterilecorridor

Wastecorridor

- 45

- 45- 30

+15

+15

+30

- 45Room pressure (Pa)

Connection to Biokill

GEP Control (Engineering steps)GMP Control (Qualification steps)Process Validation & Continuous Validation

User Requirement Brief Basic Design

Specification Phase

System Build

System Level Impact Assessment

Validation Master Plan

Design QualificationStartStart

Detailed Design

URS

Design Phase

Construction Phase

ProductionContinuous Validation

(Maintenance)

Process Validation

Post-Commissioning

Installation Qualification

Operational Qualification

Performance Qualification

Installation &Operational Phases

Performance Phase

Design QualificationCompleteComplete

Pre-Commissioning

Commissioning

GSOPBIO VAL-1204-30001

The context :The context : ““Never compromise with Quality…”Never compromise with Quality…”

Standard timing for «Greenfield » project Standard timing for «Greenfield » project 

The opportunities :The opportunities : System Level Impact AssessmentSystem Level Impact Assessment

The opportunities: The opportunities:

Parallel Commissioning Parallel Commissioning

Learning 5:Learning 5: A strong and rational qualification approach helps to reduce timing

The opportunities : The opportunities :

Renovation of existing facilitiesRenovation of existing facilities

Why is renovation a nightmare ? 

Existing facilities are usually BSL 2 , which is much less stringent in Biosafety

Unexpected « bad surprises » can delay timing (when « as build » is unfortunately not « as found »)

Commercial scale must comply with all GMP and BSL 3all GMP and BSL 3 requirements (GSK never compromises with Quality and Safety).

When renovation remains attractive ?

If footprint area remains unchanged, permitting procedure with township is much more rapid. Civil work and Permitting are on critical path.

For development and clinical trial (phase I,II,III) facilities at a smaller scale (10 L – 80L – 600L…)

ConclusionsConclusions

How engineering can help to a pandemic approach ?

1/ Build before completion of clinical trials

2/ Always build flexible (especially if process is still under development)

6/ When possible, chose renovation to speed small scales units.

3/ Anticipate purchasing of long lead equipments

4/ Use new innovative technologies

5/ Have a strong and rationale validation approach

Thank you for your attention.

Etienne Malhaize,

Director of Technical Service – Process Biotech.

Thank you for your attention.

Etienne Malhaize,

Director of Technical Service – Process Biotech.

NAE/IOMConference April 10 th , Vaccine production : Potential Engineering Approach to a Pandemic