Biologics Manufacturing Facilities of the FutureDesign Trends for Facilities in 2020

By Andy RaynerGroup Director of Technology, PM Group

18th March 2010

BioLogic Manufacturing World Asia 2010

Cell Culture Facilities global capacity being driven by mAb’s & Vaccines:

Product Trends

Source: Phrma 2008 Biotech Report

Facilities of Today

Small Scale <5,000L

Medium to Large Scale 5,000L – 10,000L

Large to Very Large Scale 10,000L – 25,000L

The Visual Factory

Superskids

In Line Dilution & Formulation

Sustainable Design Methodologies

Innovation SustainableSites

WaterEfficiency

Energy &Atmosphere

Materials &Resources

IndoorEnvironmental

Quality

A number of product trends are impacting facility design most notably:Higher Titres

Product Trends

PER.C6® Cell Line FROM CRUCELL Titres up to 27 g/L

Regulatory Trends

1978

Introduction of GMPs

Introduction of Validation

1987

1997

2003

Post approval changes to biologics processes

Multiproduct manufacturing

Transfer of many

biologics to CDER

2008

The age of Biosimilars

Yesterday

Tomorrow

Open vs Closed Processing & Multiproduct Operation

Today

The Rise of Disposables (Single Use Equipment)

Source: Based upon initial concept by Jagschies, GE Healthcare, Bioprocess International 2007

10L

100L

1,000L

10,000L

10Kg 100Kg 1,000Kg

25,000L

100,000L

3,000Kg

2,000L

Fully Dedicated Facilites(500Kg to 3,000Kg)

Concurrent Multi-Product Facilites (10Kg to 1000Kg)

Clinical Production Facilites(2Kg to 30Kg)

Stainless Steel Envelope

Disposables Envelope

Traditional Manufacturing Schematic

Buffer Hold

Buffer PrepMedia Prep

Single-UsePrep

System

BufferHold Totes

Single-UsePrep

System

`

Kim L. Nelson, Ph.D. 2006

L1

L2

L3

Seed Trains

NutrientFeeds

Clarification

VirusInactivation

ToFill /

Finish

0.22filtration

Seed Biorxt

Seed Biorxt

5,000 L Bioreactor

BreakTank

Production

HarvestTank

InactivationHold Tank Harvest

Tank

Chrom 1CIP Skid

CellInoc

Purification

UF / DFChrom 3

HarvestTank Harvest

TankHarvest

Tank

Chrom 2

Viralnanofiltration

UF / DF

CIP Skid

CIP Skid

```

```

```

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First Stage Disposables Implementation

Available Available –– Good ApplicationGood ApplicationAvailable. but must confirm process suitabilityAvailable. but must confirm process suitability

Available. but must confirm process suitabilityAvailable. but must confirm process suitabilityUnavailable at larger scalesUnavailable at larger scales

Second Stage Disposables Implementation

Single Use Equipment– Liquid Storage and Mixing

Single Use Equipment– Bioreactors, Harvest and Downstream

Reduced cleanroom floor space allocation

Space Requirements For Single Use

Reasons to Consider Disposables

Technical- Product Changover Time- Flexibility to change- Campaign Turnaround Times- Water Usage / Waste Water- Solid Waste Disposal- Leechable/Extractable Validation- Facility Size- CIP- SIP- Sustainability design

Capital Cost & Cost of Goods USA/Europe Asia USA/Europe Asia- Equipment Cost High Medium Medium Medium- Facility Cost High Low Medium Low- Cost of Goods High Medium Medium Medium- Supply Chain Solid ok Solid ok

SlowerHighLess MoreSmallLarger

FasterEasy

FasterLow

HighSmaller

SlowerPainful

Traditional Stainless Steel Technology Disposables Technology

Complex SimplerComplex Simpler

Low High

Expanded from an original concept in a table by Johannes Roebers, Senior Vice President, Biologic Strategy, Planning and Operation in Elan Pharma International Limited, presented initially to a PDA meeting in Dublin, Ireland in a paper entitled “Future Trends in Biopharmaceutical Manufacturing” and dated 25th June 2008

Building Stacking Concepts - Horizontal

HVAC

Utilities Media Preparation & Cell Culture & Support Purif ication & Buffer Preparation & WarehouseMedia Hold Harvest Bulk Fill Buffer Hold

Horizontal Production Concept 1

HVAC

Media Preparation & Cell Culture & Support Purif ication & Buffer Preparation &Media Hold Harvest Bulk Fill Buffer HoldUtilities Support Utilities Warehouse

Horizontal Production Concept 2Both allow ease of material & personnel access to all production rooms without the use of stairs or elevatorsAvoids the transfer of tubing between floorsSuitable for Single Use (Disposables) and small scale stainless steel facilities

Production all at one level

Thanks to Elan Pharmaceuticals for kind permission to use this image created by PM Group

Important Concepts for single use (disposables) facilities

5S – Sort, Set In Order, Shine, Standardize, SustainBe organised, everything has it’s place

7 (now 8) WastesOverproduction, Waiting, Transportation, Inventory, Motion (non value added), Over Processing, Rework, (Talent)

Takt TimeThe “heartbeat” of the facility, used to standardise production time of workcells for line balancing

Mistake Proofing (Poke Yoke)Ensuring that the wrong connection is not made, or wrong bag assembly is not used

Line Side Warehousing“Pull” system to Kanban supermarkets in place of pushing to inventory

Lean Manufacturing

Facilities of the PAST

Facilities of the PRESENT

Facilities of the FUTURE

Futuristic Facilities of Today

The Single-Use Facility of Tomorrow

• Bigger spaces

• Production oftenat a single level

• Lower gradecleanrooms

• Greateremphasis onLeanManufacturingprinciples

CONCLUSIONThink beyond today because tomorrow will look very different !

Credits:Peter Hanson (PM)Jordaan Kemp (PM)Peter Hanson (PM)Ian Dacey (PM)Mark von Stwolinski (CRB)Kim Nelson (CRB)Alice Redmond (PM)Johannes Roebers (Elan)Per Karlberg & John Davis (GE Healthcare)

Contact Details

Andy RaynerGroup Director of TechnologyPM GroupKillakee House,Belgard Square,Tallaght,Dublin 24,IrelandTel: +353-1-4040700E-Mail: andy.rayner@pmg.ie

Any Questions?