automating fermentation

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INTERPHEX2007 INTERPHEX2007 April 24-26, April 24-26, 2007 2007 Automating Fermentation Automating Fermentation

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INTERPHEX2007INTERPHEX2007April 24-26, 2007April 24-26, 2007

Automating FermentationAutomating Fermentation

INTERPHEX2007INTERPHEX2007April 24-26, 2007April 24-26, 2007

Presenters

Todd Ham– Automation Engineer

Emerson Process Management, Life Sciences, Food, and Beverage

Todd Edgington– Automation Engineer

Genentech

NIMO Facility, Oceanside, CA

INTERPHEX2007INTERPHEX2007April 24-26, 2007April 24-26, 2007

The NIMO Project Overview

• NIMO is a large scale, multi-product biopharmaceutical complex.

• Fermentation/Recovery process– Fermentation– Centrifuges, Chromatography, UF/DF, …– CIP/SIP

• Fully automated– Recipe-level batch control– Warehouse management– Electronic signatures– Electronic records

INTERPHEX2007INTERPHEX2007April 24-26, 2007April 24-26, 2007

The NIMO Project Timeline

NIMO Engineering Kick-Off

Procurement

Construction

Commissioning

Validation

BLA Enabling Runs

BLA Submission

FDA Review

BLA Approval

Engineering and Design

2000 2002 2004 2006 2008

INTERPHEX2007INTERPHEX2007April 24-26, 2007April 24-26, 2007

NIMO Philosophy• Fully automated

• Paperless, dock-to-dock

– Electronic record

– Handheld units for plant operations

– Barcode scanning for material additions, filters

• Consistency for operator / Use of industry standards

– Bus technologies

– S88 / S95

• Fermentation was integral to entire project

– Project philosophy impacted fermentation

– Fermentation impacted project philosophy

INTERPHEX2007INTERPHEX2007April 24-26, 2007April 24-26, 2007

The Fermentation Process Overview

Vent through

roof

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CIPS/CSL310

CIPS/CSL311

SPARGE GAS (CA)

SPARGE GAS (CA)

OVERLAY GAS (CA)

TO MEDIA FILTER

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T

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CIPS/CSL311-R2-1560-B

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FERMENTER

InoculationPressure Control

Media

Sampling

Additive

Base

Sparge

CIP/SIPFeed Vessel (for Large Fermenters)

INTERPHEX2007INTERPHEX2007April 24-26, 2007April 24-26, 2007

S88 Control Modules

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CIPS/CSL303

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F-15X0.A

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T

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TE237

P

P P

P

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XV032

XV034

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P P

P

P P

XV100

XV101

XV103

TTE102

P

VA-15X0.B

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MV110

T

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T

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T

XV129

XV131

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P P

P

P P

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P

VA-15X0.C

CIPS/CSL309

MV135

T

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T

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T

CIPS/CSL311

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Feed Media

CIPS/CSL

Vent

Media

Overlay

Sparge1

Sparge2

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T

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P P

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Product

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310

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CMB 3/3/03

CIPR

• Identify the “common” modules and instances.

Examples: Motors Valves

INTERPHEX2007INTERPHEX2007April 24-26, 2007April 24-26, 2007

S88 Equipment Modules

• Used some project-wide module templates– Sampling System– Sparger Control

• Added some area-specific module templates– Fermentation Agitator Control– Fermentation Pressure Control– Fermentation Temperature

Control– pH Control– Dissolved Oxygen Control– Foam Control

• Added unique (one-time use) equipment modules– Transfer Panels– Valve Assembly (VA) Control

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INTERPHEX2007INTERPHEX2007April 24-26, 2007April 24-26, 2007

Transfer Panel

INTERPHEX2007INTERPHEX2007April 24-26, 2007April 24-26, 2007

S88 Units

• Identify classes and instances based on..– Physical similarity– Phases that they use

• Batch Media

• Inoculate

• Ferment

• Etc.Unit Class: Production Fermenter

TP A TP B

Unit Class: Seed FermenterUnit Class: Inoc Fermenter

VAUnit Class: Feed Vessel

INTERPHEX2007INTERPHEX2007April 24-26, 2007April 24-26, 2007

Phase Control

• Batch Feed Vessel• Batch Fermenter• Pre-inoculation Prep• Inoculate• Ferment• Sample• Add Additive• Add Base• Add Feed Media• Transfer• Pressure Test

• The following CIP Phases for Feed Vessel, Production Fermenter, Seed Fermenter, Discharge Line, and Media Line

– CIP Setup– CIP Circuit– CIP Complete

• Pre-SIP Pressure Test Seed Fermenter

• Pre-SIP Pressure Test Production Fermenter

• Pre-SIP Setup• SIP Sample Line• SIP Production

Fermenter• SIP Inoculation Line

INTERPHEX2007INTERPHEX2007April 24-26, 2007April 24-26, 2007

Recipes BatchFermenter

Pre-Inoculation Prepare

SIP Inoculum Line

Inoculation

Fermentation

Feed Media Addition

Transfer

Prompt Operator to Run:

Feed Vessel Fill Procedure

Production Fermenter Procedure

To HarvestHARVEST VESSEL

HARVEST

Vessel/Transfer Line WFI Flush

Vessel/Transfer Line WFI Flush

Base Addition

From MediaMEDIA TRANSFER

From Seed Fermenter

TRANSFER

From MediaVESSEL/TRANSFER LINE

WFI FLUSH

From MediaVESSEL/TRANSFER

LINE WFI FLUSH

Additive Addition

Prompt Operator to Run:

Media Feed CIP/SIP Procedure

Feed Addition

From MediaMEDIA TRANSFER

Wait Until Feed Vessel Fill Procedure Completes

Wait Until Media Feed CIP/SIP

Procedure Completes

1) Group Phases into Operations

2) Group Operations into Unit Procedures

3) Group Unit Procedures into Procedures

INTERPHEX2007INTERPHEX2007April 24-26, 2007April 24-26, 2007

Vessel to Vessel Communication

T

T

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SEED FERMENTER

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PRODUCTIONFERMENTER

TP

Are you ready to receive?

Yes. Bring it on.

Here comes the transfer.

I got it.

INTERPHEX2007INTERPHEX2007April 24-26, 2007April 24-26, 2007

Manufacturing Procedures

• Material Management

• Container Management

• Filter Management

• Sampling

MAT 2.200 GR

INTERPHEX2007INTERPHEX2007April 24-26, 2007April 24-26, 2007

Testing

• Emerson and Genentech worked together closely on requirements

• Emerson performed module-level and integration–level testing

• Emerson and Genentech ran a full Customer Acceptance Test (CAT) prior to delivery

INTERPHEX2007INTERPHEX2007April 24-26, 2007April 24-26, 2007

Lessons Learned – Modularity

• As much as possible, keep process units the same.

• With similar units, make sure operations are as uniform as possible as well!

• Beware of alias over-load.

• Enforcement of classes can be a negative thing.

Unit Class: Seed Fermenter

INTERPHEX2007INTERPHEX2007April 24-26, 2007April 24-26, 2007

Lessons Learned – Level of Automation

• High levels of automation are a double edged sword.

• With high levels of automation and modularity, documents can become very numerous.

INTERPHEX2007INTERPHEX2007April 24-26, 2007April 24-26, 2007

Lessons Learned – Up-Front Testing

• Time spent upfront saves on back end effort.

• Easier to fix problems off-site when you are in control of the software.

• Risk based software validation works.

• No level of testing will capture all mistakes or prevent changes.

INTERPHEX2007INTERPHEX2007April 24-26, 2007April 24-26, 2007

Lessons Learned – Raw Material Handling and other Manufacturing Procedures

• Make sure everyone is on the same page from the start.

• Make sure everyone uses the same language.

• Get operators time on the equipment.

INTERPHEX2007INTERPHEX2007April 24-26, 2007April 24-26, 2007

Conclusion

• Leverage the S88 model as much as possible.

• Take as much time as possible upfront.

• Prepare for an effort commensurate with your level of automation.

Right-SizeRight-Size

INTERPHEX2007INTERPHEX2007April 24-26, 2007April 24-26, 2007

Acknowledgements

Genentech• Johannes Roebers• Christoph Lebl• Dave Stewart• Sean Stephan• Debi Marshall• Christopher Birnie• Leonidas Castaneda• Jim Merrit• Dirk Ellison

Emerson• Christie Deitz• Craig Bieda• Brian Crandall• Molly Firkins• Dick Seeman• Chen Yang• Shelley Richards• Ajay Savargaonkar• Ketaki Raste