sample title/divider slide - add title here · 2017-10-21 · •internet of things • reduced...

The project delivery specialists

Factory of the Future

vision. The project delivery specialists

Agenda

2

• Drivers

• Identifying Areas To Improve

• How are we doing as an

industry?

• Enabling Technologies &

Game Changers

• Test Case

Today is focused on Pharms

industry......In production

efficiency terms, pharms is

behind food and other

industries.

AREA

HOW

DRIVE TECH

TEST



Drivers

committed. The project delivery specialists

Drivers

4

Price pressure from pharmaceutical purchase groups in China & globally

Patent cliffs and the rise of generics and biosimilars putting pressure on company margins

Need to reduce energy costs and carbon footprint to meet strategic objectives of client seduce cost of goods

The rise of metrics to measure individual site performance (operational excellence). Sometimes on-line!

Need to reduce cost of goods Movement of the pharmaceutical industry turnover from small to large molecules

Biopharmaceutical start-ups need to reduce capital costs, to reduce time to break even

More established companies will look more closely at cost of goods

Policy encouragement Similar successful test case

COST

TECH

PATENT SCALE

POLICY



Identifying Area To Improve?

5

efficient. The project delivery specialists

Reducing Costs

Blockbuster are increasingly hard to

find

Patent cliff affecting revenue

Cost pressure from purchasers (e.g.

China/UK/Germany)

Reduce Manufacturing

Costs

Reduce Company

Overheads

Reduce R&D Costs

Reduce Manufacturing

Costs

Rationalize plants worldwide

Lower Cost Country

Reduce costs in current or

new plant

How Can Manufacturing Costs Be Reduced?

CMOs

Does Manufacturing Efficiency Affect Margin? 1 of 2

Company Level – Manufacturing Av 49.4%, Margin 14.8%

R&D Driven Companies

Generics Manufacturer

Contract Manufacturer

0.0%

10.0%

20.0%

30.0%

40.0%

50.0%

60.0%

70.0%

R&DManufacturing

General &Administration Sales &

Marketting Margin

Operational Excellence Friedli 2006, >100 plants

Company Level Costs

Does Manufacturing Efficiency Affect Margin 2 of 2

Manufacturing Costs, Circa 50% are fixed

Plant Level Costs

Other Costs 16%

Labor Cost Indirect

12%

Labor Cost Direct 13% Plant,

Property & Equipment

15%

Cost Of Material

44%

Operational Excellence Friedli 2006, >100 plants

Tools For Identify Areas To Improve

Operational Excellence Initiative

• Mainly initiated in Europe

• Focus on Key performance

indicators and comparisons to

improve efficiency

• ‘Incorporates’ Lean

• Also deals with global product

transfer

• Uses logics and math's to justify

decisions

• KPI and OEE monitoring drives

attention into right areas quickly

Special Mention – Lean & Six Sigma

Messages I Take From Operational

Excellence Mathematics

OUTPUT

• Output is the most important thing, (for the rate determining equipment), measured by OEE (Overall equipment effectiveness)

EQUIPMENT

• What happens when the equipment is not producing is more important (and more variable between companies/sites) than when it is.

INVENTORY

• Inventory is a huge ‘hidden’ cost, you need to justify why you need 12 months inventory and not 3 or 6 months. Times and procurement systems have changed, take advantage of this.

IMPROVEMENTS

• Small improvements to the existing plant, or in the design of a new plants can lead to surprisingly large margin gains. The extra 3-5% output is worth chasing



How is the Industry Doing?

experienced. The project delivery specialists

Facility of the Future Attributes

Flexible

Cost Effective

(OPEX)

Adaptable

Configurable Scalable

Responsive

Mobile

Facility of

the Future

All Plants Are Not Equal

Quote ‘Good sites produce twice as much as poor sites’

Factors Affecting Plant Efficiency

•Manufacturing procedures incl. Changeover/clean

•Management procedures (Delays due to permissions)

•Equipment Breakdown

•Fundamental Design

Operational Excellence Verlag 2006, >100 plants

Plants Worldwide Are Becoming More Efficient

Operational Excellence Verlag 2012

Pharmaceutical Production and Packaging

Friedl 2013

Low hanging fruit , operational inefficiencies are being dealt with,

Standing Still is not an option! -

A site that wants to compete must keep up, salaries are increasing in China

it is important to stay ahead.

HOW TO DO - Games Changers 1

16

• German Industry 4.0 initiative

• Internet of Things

• Reduced manpower levels, to compete with low cost

manufacturing centers

• Continuous OSD Production (and PAT)

• Continuous mixers

• Continuous granulators/melt extrusion devices GEA Consigma,

Bohle & Others, new granulation technologies

• Roller compactors….we have had these for a long time…

• Tablet Presses… we have had these for a long time

• Continuous Fill Finish – Are we far away?

• New modularities, Cell therapy, fusion protein.

• Modular ‘Off the shelf’ Buildings (The holy grail)

• GE Kubio

• New product release technologies

• Disposables standardization

• Dance floor vs. Ballroom

Internet of Things

Reduced manpower levels, to compete with low cost manufacturing centers

Continuous OSD Production (and PAT)

Continuous mixers

Continuous granulators/melt extrusion devices GEA Consigma, Bohle & Others, new granulation technologies

Roller compactors….we have had these for a long time…

Tablet Presses… we have had these for a long time

Continuous Fill Finish – Are we far away?

New modularities, Cell therapy, fusion protein.

Modular ‘Off the shelf’ Buildings (The holy grail)

GE Kubio

New product release technologies

German Industry 4.0 initiative / Internet of Things

Continuous Production

New modularity, Cell therapy, fusion protein

New product release technologies

Disposables standardization

New Design Concept – Dance floor vs. Ballroom

HOW TO DO - Games Changers 2

17

• On line measurement technologies

• Disposable instruments

• Increased speed of global process transfer, increased

corporate reliance on site KPI’s.(driving standardization

of process equipment)

• OpEx drivers e.g. Inventory, time on plant

(Procurement monitoring technologies)

• PAT

On line measurement technologies

Disposable instruments

Vial in tub filling technologies… A quiet revolution

Increased speed of global process transfer

OpEx drivers e.g. Inventory, time on plant (Procurement monitoring technologies)

Are We In The Fourth Industrial Revolution?

Industry 4.0

19 Graphic From Christoph Roser at http://www.allaboutlean.com

http://www.allaboutlean.com/



Enabling Technologies – Game Changers

master.. The project delivery specialists

GEA ConsiGma Continuous Tablet Line (CTL)

Wet Granulation (10 to 40 Kg/hr)

23

Blender for compression blend Granule Milling Raw materials feed

Screw

Granulation &

Segemented

Drying

Multi-function tablet press

Pilot Plant Mezzanine Single Room Stack-Up

(Circa 8m)

Option for vacuum transfer or

Mueller type 100l bins

Option for contained API transfer using

flexibiles and Ezidock/Buck Hycoflex or

SBV technology

Ktron Feeder

(Note next size up significantly taller height)

Note low ceiling height below mezanine,

2.6m (Care needed for lights, spinklers,

instruments and HVAC)

Press may be replaced with other unit

operations, roller compactor, capsule filler

or IBC for blending trials

Fette ‘Direct To Press’ Magnesium Stearate Additions

Unit (Removes a final blending step)

Fette PKB2

Fette PKB3

Note uses compressed air for fluidised MS

transport and hasn’t been used for a

contained/isolated press

Uses volume or weight & double screw feeding

Typical Cell Culture Manufacturing Schematic

VENT

Innoculum Scale-UpProduction

Bioreactors

Media Hold Vessels

0.2 micron filtersDepth FiltersCentrifuge

CHROM 1 CHROM 2 CHROM 3

UF/DF

VIRAL FILTRATION

SKID

FINAL

FILTRATION

FINAL PRODUCT

LAMINAR FLOW HOODUF/DF 4

F

Harvest

Tank

Media Preparation Vessels

NutrientAntifoam

Buffer Hold Vessels

Buffer Preparation Vessels

UPSTREAM

DOWNSTREAM

pH ADJUST

Initial Disposables Implementation

VENT


Bioreactors

Media Hold Vessels



UF/DF

VIRAL FILTRATION

SKID

FINAL

FILTRATION

FINAL PRODUCT


F

Harvest

Tank


NutrientAntifoam

Buffer Hold Vessels


UPSTREAM

DOWNSTREAM

pH ADJUST

Significant Disposables Implementation

VENT


Bioreactors

Media Hold Vessels



UF/DF

VIRAL FILTRATION

SKID

FINAL

FILTRATION

FINAL PRODUCT


F

Harvest

Tank


NutrientAntifoam

Buffer Hold Vessels


UPSTREAM

DOWNSTREAM

pH ADJUST

Liquid Storage and Mixing Systems

Scale of Operations

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

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

In Line Dilution

Make Vessels Smaller - Dilute when you need it


Ready Packed Disposable Chromatography

Columns – Remove Column Packing Room


Client view – Often want to take out operations from the plant to ‘lower cost facilities’

Client Blind Spot - Just because it is done somewhere else it doesn’t means it magically

100% correct

E.g. 1 - Merck Millipore do final assembly in D or C on a table, laminar flow would be

better to remove bio-burden

E.g. 2 West do washing of stoppers in CNC, clients always do it in D or C

E.g. 3 Hyclone has had cross contamination issues in US for powder filling

Components – Nested & Bulk

35

Schott (SyriQ/AdaptiQ) Nuova Ompi (EZ-Fill) BD (HYPAK SCF)

http://www.ebay.com/itm/100-X-20ml-Headspace-Crimp-Vial-clear-rounded-bottom-100-pack-With-Caps-/292000212874

Vanrx SA25 Aseptic Workcell

36

Capabilities:

< 1 tub/min

Multiple Formats

Vial 2 to 50ml

Syringe 0.5 to 20ml

Cartridge up to 5ml

Modules for integrated

VHP Decontamination

Chamber

Automatic Delid / Deliner

Capping https://vanrx.com/technology/

https://vanrx.com/technology/

Modular Technology - Pfizer working with GEA

and G-Con to development deployment PODS

38

Status

• FAT process skid

was Sept 2014

• Delivery to Groton

Dec ‘14

• Commission Q1 ‘15

• Operational Q2 ‘15

Ref: ISPE Annual Meeting 2014 – presentation by Rick Mitzner, Senior Director, Engineering Technology

Modular Beigene – Kubio Modules

Modular Just Bio



Test Case - Single Use Factory Of Future Requirements

expertise. The project delivery specialists

Example: Single-Use Facility

Factory of the future Impact

Current designs E

ne

rgy c

osts

Wa

ter

Co

sts

Co

nsu

ma

ble

co

sts

He

ad

co

un

t

Bu

ild c

osts

Inte

gra

tion

co

sts

En

erg

y c

osts

Headcount

Wa

ter c

osts

Factory of the future



En

erg

y c

osts

Wa

ter

Co

sts

Co

nsu

ma

ble

co

sts

He

ad

co

un

t

Bu

ild c

osts

Inte

gra

tion

co

sts

The ability for plug and play will

become critical. This means

that suppliers will need to

generate ‘standardised‘

automation that allows easy

integration of skids into an

overarching control system


Real-time Release

Interchangeable

Skids

SID Standard Interface Design

Autonomous sampling

Marvin

Integration Of Equipment Connection

Automation & Integration Of Equipment Connection Big Problems Solved By Small Things

Disorder is not good engineering

practice

& 1st Impressions count

Falcon Tubing & Artison Valves

For Changing over the media bag

in the middle of the night



En

erg

y c

osts

Wa

ter

Co

sts

Co

nsu

ma

ble

co

sts

He

ad

co

un

t

Bu

ild c

osts

Inte

gra

tion

co

sts

• Smaller facility

• Lower air changes

• Off the shelf skids

• Conc. Buffer = smaller

tanks

• Less utilities

• No Autoclave

• Generic designs

• Smaller warehouse


-vs-

Ballroom

Dancefloor

Static Totes.

Defined Tubing Paths.

The 3 metre rule.

No trip Hazards.

Ability to Automate.

Facility engineered to be lean.

Smaller footprint.

Less HVAC costs.


Ballroom –vs- ‘PM Initiative’ Dancefloor



En

erg

y c

osts

Wa

ter

Co

sts

Co

nsu

ma

ble

co

sts

He

ad

co

un

t

Bu

ild c

osts

Inte

gra

tion

co

sts

• Less steam usage

• Less HVAC

• Less People

• Less space to heat




En

erg

y c

osts

Wa

ter

Co

sts

Co

nsu

ma

ble

co

sts

He

ad

co

un

t

Bu

ild c

osts

Inte

gra

tion

co

sts

• Less Clean in Place

• Less steam





En

erg

y c

osts

Wa

ter

Co

sts

Co

nsu

ma

ble

co

sts

He

ad

co

un

t

Bu

ild c

osts

Inte

gra

tion

co

sts

• Standardisation

• Lower cost

• Faster lead times

• Mass production

• More reliability

Standardising Disposables - Defining the problem

• Time spent designing parts

• Connectivity between multiple

suppliers parts

• Always reinventing wheel

• Supply chain is often last to

know

• Long design times

• Large warehouses

• Long lead times

Standardising Disposables

How does this benefit The end user?

• Faster delivery times

• Smaller warehouse

• Like for like comparisons for

multiple options

• Faster design

• Prices gained early in the

project


Connected Processing

56

• Optimizing Space and Production Throughput

• Multiple Unit Operations connected together without collecting

the entire batch and holding from prior step

• Use of small surge bags

• A part of the solution towards Continuous Processing

• Utilization of PAT for Feed Forward-Feed Back control

50L Bag

Chrom Skid3000L Bag

Viral Reduction Step

50L Bag

3000L BagChrom Skid



En

erg

y c

osts

Wa

ter

Co

sts

Co

nsu

ma

ble

co

sts

He

ad

co

un

t

Bu

ild c

osts

Inte

gra

tion

co

sts

• Current trend

• Facilities designed to

operate with mainly day

staff


Example: Single-Use Facility Challenges

Resistance to change from end users

• Suppliers will buy-in if end users start changing their buying

habits.

• Reliability of equipment to run overnight

• Introduction of the ballroom environment to allow unhindered

access

• Introduction of pinch valves

• Powder containment

• QC & QA need to be reduced as well

• Normalization of room grades to level the playing field (Need more

open/closed risk analysis to be done, see ISPE baseline Guide)

The future plants are here now! Standing still is not an option

Two Paths

Both Need Well Designed Operational Practices & Well Designed Plants

sample title/divider slide - add title here · 2017-10-21 · •internet of things • reduced...

Documents