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

Morten Munk NNE Flexibility by Design February 27 - March 2, 2017 San Francisco, CA

TRENDS – A LITTLE QUIZ 2

Trends • 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 3

Trends – cont. • Tech Transfer • Continuous processing Level 1 Real-time automatic control + Flexible process • Control Strategy parameters to respond to the variability in the input material attributes Level 2 Reduced end product testing + Flexible critical material attributes and critical process parameters within design space • Devices Level 3 End product testing + tightly constrained material attributes and process parameters • Environmental impact • ADC’s 4

THE NEW PHARMA REALITY… 5

The New Pharma Reality… The new pharma reality… 6

The future ”long tail” of therapeutic areas 12th Annual report and survey of biopharmaceutical manufacturing capacity and production Eric S. Langer, MS, President, Orphan drugs catch BioPlan Associates, Inc. fire in big pharma PM360 July 2015 7

The New Pharma Reality… The new pharma reality… Today’s product Last century product distribution distribution Focus on manufacturing Focus on change-over Speed speed 8

The new pharma reality… Robotics • 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 Robots/10,000 employees Source IFR: World robotics 2016

FACILITY CONSIDERATIONS 10

Product Supply Options 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 of the expected demand 11

Pr Produ oduct ct Sup Suppl ply y With ith a NPV a NPV Focu ocus Net present value (NPV) is key driver for the business decision Internal cost Cost of Plant Facility and Total incorporating Lost revenues productivity investment project staff flexibility and from delayed Utilization Qualification cost cost of lack of market entrance Change-over TIC Raw Materials flexibility time Utilities IT NPV Project Contingencies Risk of product not schedule Future revenues The known Cost of capital being approved for Timeline from from sales unknowns the market decision to Project changes approval 12

Facility design Distribution of demand for different batch sizes Normal distribution Product demand Batch size 13

Facility design Distribution of demand for different batch sizes Product demand Batch size 14

Facility design Distribution of demand for different batch sizes - API product Orphan drug Insulin Product demand Batch size 15

Facility design Distribution of demand for different batch sizes – Final drug product Luxemburg USA Product demand Batch size 16

Build in flexibility Suite Site and Process level Operations Investment configuration integration flexibility flexibility flexibility flexibility flexibility 17

BASIC PROJECT CONSIDERATIONS 18

What comes first – Facility consideration • Layout • Equipment • Classification • Process • Segregation • Closed / open • HVAC • SS / SUS • Organisation – People and processes • Procedures – SOP’s, gowning, planning • Flow – People, Raw Mat, Waste • Automation, training 19

What comes first – Facility consideration • Layout • Equipment • Classification • Process • Segregation • Closed / open • HVAC • SS / SUS • Organisation – People and processes • Procedures – SOP’s, gowning, planning • Flow – People, Raw Mat, Waste • Automation, training 20

FACILITY DESIGN 21

Site Master plan 22

Building Typology – Flexible design for future expansion 23

Building Typology – Functions 6 2 3 4 5 1 1. Basic production process structure. 2. – 6. Support functions. • Administration, Main gowning, etc. • Receive / Dispatch. • Laboratories. • Utility – black / clean. • Hazardous support 24

The U-turn is an option for fast build times • Simplification of facility: • Classifications based on closed systems and risk assessment Process systems • Gravity flow not design driver (reduce vertical complexity) installation • Box in box: • Same level installation: ‘push’ process modules in • Maximizing installation interfaces for parallel execution Support systems Process • Closing the process: installation systems • Increasing trend towards CNC and Grade D installation • Increasing regulatory focus on process closure • Definitions of open/closed – Functional Closed Process systems installation 25

SINGLE USE AND THE HYBRID APPROACH 26

Enablers for flexible manufacturing Single use technology CIP/SIP STAINLESS STEEL SINGLE USE 350 L 1000 L 27

Open Mind Regarding Technology Choice TRADITIONAL SINGLE USE STAINLESS STEEL THE PRAGMATIC TECHNOLOGY GUY GUY GUY 28

Comparing stainless steel and single use 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 29

Pas ast t & Cur & Curren ent t Pr Proc oces esse ses Past and current processes From large scale stainless steel to single-use and / or continuous processing or hybrid • De-risking • Higher flexibility • Faster turn-around • Closed systems • Advanced PAT • Smaller footprint • Best of both worlds • Flexibility Hybrid facilities • Meeting broad range of demand 30

Hybrid facility - 2 parallel engines Production section - Target for facility section Typical use ‘engine technology’ Single use section Reducing investment cost Clinical and Launch Flexibility Changing production schedule Stainless steel section Reducing operation costs Commercial supply Increasing capacity Stable production scenarios 31

CONTINUOUS PROCESSING 32

Upstream – Semi continuous 8 x 2,000L DSP 1 DSP 2 DSP 3 Bulk 15,000 L DSP 1 DSP 2 DSP 3 Bulk 15,000 SS Bioreactor 8 times 2,000L SUS Bioreactors • Harvest every 16 days • Harvest every second day • One batch upstream (UPS) and downstream • 8 smaller batches, which might be combined (DSP) – less QA/QC work • Small and more flexible equipment – Media, • Large equipment – Media, buffer, UPS and buffer, UPS and DSP • Possible to have higher utilisation DSP • DSP stands idle more 50% of the time • Higher flexibility depending on demand • Low fluctuation in workload • Low fluctuation in workload

A Simple Exa A Simple Example mple – In In-li line ne Dilution Dilution A Simple Example – In-line Dilution Concept • Prepare process buffers “just in time” and Traditional at “point of use” Point of use Buffer prep. Buffer hold • Mix buffers using one (or more) concentrated 10.000L 10.000L stock solutions with water Process 1% salt 1% salt equipment 1% salt Advantages • 30 – 70 % reduction in buffer vessel size Larger flexibility in meeting future volume requirements. • Option to move from SS to SUS 10 X buffers Buffer prep. Buffer hold Water Optional Point of use conditioning 1,000 L 1,000 L 100L 10% salt 10% salt Challenges break tank Process • Concentrated buffers might be more corrosive Air gab equipment 1% salt • Temperature and pH changes during mixing 9 vol. 1 vol. • Generation of air during mixing • More complex system to establish 34

MODULAR APPROACH 35

Modular – different definitions 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 36

Modular thinking 6 2 3 4 5 Air Handling 37

Modular thinking 6 2 3 4 5 1 38

Layout – 3D Air Handlin g 6 2 3 4 5 1 39

Modular thinking Façade - Adapted to local rules and building traditions. 2 3 4 5 Technical support modules – HVAC etc. 1 Technical distribution modules. Process area – Process and Support building modules. Foundations – for building modules and Technical distribution (water, drains, waste etc.) 40

CONCLUSION 41