Design February 27 - March 2, 2017 San Francisco, CA TRENDS A - - PowerPoint PPT Presentation

Flexibility by Design

Morten Munk NNE

February 27 - March 2, 2017 San Francisco, CA

TRENDS – A LITTLE QUIZ

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• Multi product - flexible facilities
• Hybrid facilities
• 2- 8 times 15K SS
• 2- 8 times 2K SUS
• SS and SUS
• Closed processing
• Robotics
• Modular design
• Local manufacturing (and development)

in emerging markets

Trends

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Trends – cont.

• Tech Transfer
• Continuous processing
• Control Strategy
• Devices
• Environmental impact
• ADC’s

THE NEW PHARMA REALITY…

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The New Pharma Reality…

The new pharma reality…

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12th Annual report and survey of biopharmaceutical manufacturing capacity and production

Eric S. Langer, MS, President, BioPlan Associates, Inc.

Orphan drugs catch fire in big pharma PM360 July 2015

The future ”long tail”

• f

therapeutic areas

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Focus on manufacturing Speed Focus on change-over speed Last century product distribution

The New Pharma Reality…

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Today’s product distribution

The new pharma reality…

• Robot density – 2015 (all industries)

China has a robot density of just 36 – but they aim for a density of 150 by 2020 An increase of 600,000 industrial robots by 2020 Robot sales was globally 254,000 in 2015

Source IFR: World robotics 2016

Robots/10,000 employees

The new pharma reality… Robotics

FACILITY CONSIDERATIONS

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Product Supply Options

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1. Get all product produced at CMO’s 2. Co-invest in construction of new facilities together with a CMO 3. Build own facility covering all or a portion

• f the expected demand

NPV

Total investment cost TIC Internal cost Facility and project staff Qualification Raw Materials Utilities IT Cost of incorporating flexibility and cost of lack of flexibility Project schedule Timeline from decision to approval Plant productivity Utilization Change-over time Contingencies The known unknowns Project changes Cost of capital Risk of product not being approved for the market Lost revenues from delayed market entrance Future revenues from sales

Pr Produ

• duct

ct Sup Suppl ply y With ith a NPV a NPV Focu

• cus

Net present value (NPV) is key driver for the business decision

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Batch size

Facility design

Distribution of demand for different batch sizes

Product demand

Normal distribution

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Facility design

Distribution of demand for different batch sizes

Batch size Product demand

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Orphan drug Insulin

Facility design

Distribution of demand for different batch sizes - API product

Batch size Product demand

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Luxemburg USA

Facility design

Distribution of demand for different batch sizes – Final drug product

Batch size Product demand

Build in flexibility

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Process level flexibility Operations flexibility Suite configuration flexibility Site and integration flexibility Investment flexibility

BASIC PROJECT CONSIDERATIONS

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What comes first

– Facility consideration

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• Layout
• Classification
• Segregation
• HVAC
• Equipment
• Process
• Closed / open
• SS / SUS
• Organisation – People and processes
• Procedures – SOP’s, gowning, planning
• Flow – People, Raw Mat, Waste
• Automation, training

What comes first

– Facility consideration

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• Layout
• Classification
• Segregation
• HVAC
• Equipment
• Process
• Closed / open
• SS / SUS
• Organisation – People and processes
• Procedures – SOP’s, gowning, planning
• Flow – People, Raw Mat, Waste
• Automation, training

FACILITY DESIGN

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Site Master plan

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Building Typology – Flexible design for future expansion

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1 2 3 4 5 6

1. Basic production process structure.

• 2. – 6. Support functions.
• Administration, Main gowning, etc.
• Receive / Dispatch.
• Laboratories.
• Utility – black / clean.
• Hazardous support

Building Typology – Functions

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The U-turn is an option for fast build times

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• Simplification of facility:
• Classifications based on closed systems and risk assessment
• Gravity flow not design driver (reduce vertical complexity)
• Box in box:
• Same level installation: ‘push’ process modules in
• Maximizing installation interfaces for parallel execution
• Closing the process:
• Increasing trend towards CNC and Grade D
• Increasing regulatory focus on process closure
• Definitions of open/closed – Functional Closed

Support systems installation Process systems installation Process systems installation Process systems installation

SINGLE USE AND THE HYBRID APPROACH

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Enablers for flexible manufacturing

Single use technology

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STAINLESS STEEL SINGLE USE 350 L 1000 L CIP/SIP

TRADITIONAL STAINLESS STEEL GUY THE PRAGMATIC GUY SINGLE USE TECHNOLOGY GUY

Open Mind Regarding Technology Choice

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Stainless steel Single Use Scale Capital – investment – CAPEX Capital – operational costs – OPEX Minimise risk of (cross) contamination Time for establishing a facility Flexibility Change over time Commission and qualification Leachables Ease to tech transfer Sustainability

Comparing stainless steel and single use

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• De-risking
• Higher flexibility
• Faster turn-around
• Closed systems
• Advanced PAT
• Smaller footprint

Pas ast t & Cur & Curren ent t Pr Proc

• ces

esse ses

Past and current processes

From large scale stainless steel to single-use and / or continuous processing or hybrid

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• Best of both worlds
• Flexibility
• Meeting broad

range of demand

Hybrid facilities

Hybrid facility - 2 parallel engines

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Production section - ‘engine technology’ Target for facility section Typical use Single use section Reducing investment cost Flexibility Clinical and Launch Changing production schedule Stainless steel section Reducing operation costs Increasing capacity Commercial supply Stable production scenarios

CONTINUOUS PROCESSING

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Upstream – Semi continuous

15,000 SS Bioreactor

• Harvest every 16 days
• One batch upstream (UPS) and downstream

(DSP) – less QA/QC work

• Large equipment – Media, buffer, UPS and

DSP

• DSP stands idle more 50% of the time
• Low fluctuation in workload

8 times 2,000L SUS Bioreactors

• Harvest every second day
• 8 smaller batches, which might be combined
• Small and more flexible equipment – Media,

buffer, UPS and DSP

• Possible to have higher utilisation
• Higher flexibility depending on demand
• Low fluctuation in workload

15,000 L DSP 1 DSP 2 DSP 3 Bulk 8 x 2,000L DSP 1 DSP 2 DSP 3 Bulk

A Simple Example – In-line Dilution

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Concept

• Prepare process buffers “just in time” and

at “point of use”

• Mix buffers using one (or more) concentrated

stock solutions with water Advantages

• 30 – 70 % reduction in buffer vessel size

Larger flexibility in meeting future volume requirements.

• Option to move from SS to SUS

Challenges

• Concentrated buffers might be more corrosive
• Temperature and pH changes during mixing
• Generation of air during mixing
• More complex system to establish

A Simple A Simple Exa Example mple – In In-li line ne Dilution Dilution

Buffer prep. 1,000 L 10% salt Buffer hold 1,000 L 10% salt Optional conditioning 100L break tank Water 9 vol. 1 vol. Point of use Process equipment 1% salt Air gab 10 X buffers Buffer prep. 10.000L 1% salt Buffer hold 10.000L 1% salt Point of use Process equipment 1% salt Traditional

MODULAR APPROACH

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Modular – different definitions

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Modular – Copy / Paste

• On-site construction, where same type of rooms are build as copies

– same size and configuration Modular – off site construction of building elements – LEGO concept

• A method of construction that utilizes off-site pre-engineered,

pre-fabricated structures which are reassembled on-site.

• Up to 100% of the building and the equipment are already completed

and pre-tested at the factory prior to shipping Modular - PODular

• Full clean-room facilities built in a POD, including HVAC, air locks etc., which

is build and qualified off-site. The POD’s are then shipped to the site for the pharmaceutical production and connected to the stick built part of the facility

Modular thinking

2 3 4 5 6

Air Handling

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Modular thinking

1 2 3 4 5 6

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Layout – 3D

1 2 3 4 5 6

Air Handlin g

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Modular thinking

1 2 3 4 5

Façade - Adapted to local rules and building traditions. Technical support modules – HVAC etc. Technical distribution modules. Process area – Process and Support building modules. Foundations – for building modules and Technical distribution (water, drains, waste etc.)

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CONCLUSION

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Future – Possibilities

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• Multi product flexible facilities
• Prepared for future expansions and new products
• Hybrid facilities – Motorway and city roads
• Optimal use of SUS, Continuous Processing and other “new” technologies
• Closed processing
• Lower area classification – few airlocks – larger suits
• “Modular” facility designs
• Flexibility – standardisation – simplification

Thank you

Morten Munk Global Technology Partner NNE A/S mbmn@nne.com Mobile: +45 3079 2254